Benzamide derivatives useful as histone deacetylase inhibitors

ABSTRACT

The invention concerns a compound of the formula (I) wherein Ring A is heterocyclyl; m is 0-4 and each R 1  is a group such as hydroxy, halo, trifluoromethyl and cyano; R 2  is, halo and n is 0-2; and each R 4  is a group such as hydroxy, halo, trifluoromethyl and cyano; p is 0-4; and R 3  is amino or hydroxy; or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by histone deacetylase.

This invention relates to benzamide derivatives, or pharmaceuticallyacceptable salts or in vivo hydrolysable esters or amides thereof. Thesebenzamide derivatives possess histone deacetylase (HDAC) inhibitoryactivity and accordingly have value in the treatment of disease statesassociated with cancer (Marks et al., Nature Reviews, 1, 194-202,(2001)), cystic fibrosis (Li, S. et al, J. Biol. Chem., 274, 7803-7815,(1999)), Huntingdons chorea (Steffan, J. S. et al., Nature, 413,739-743, (2001)) and sickle cell anaemia (Gabbianelli, M. et al., Blood,95, 3555-3561, (2000)), and accordingly are useful in methods oftreatment of a warm-blooded animal, such as man. The invention alsorelates to processes for the manufacture of said benzamide derivatives,to pharmaceutical compositions containing them and to their use in themanufacture of medicaments to inhibit HDAC in a warm-blooded animal,such as man.

In the eukaryotic cell, DNA is compacted to prevent transcription factoraccessibility. When the cell is activated this compact DNA is madeavailable to DNA-binding proteins, thereby allowing the induction ofgene transcription (Beato, M., J. Med. Chem., 74, 711-724 (1996);Wolffe, A. P., Nature, 387, 16-17 (1997)). Nuclear DNA associates withhistones to form a complex known as chromatin. The core histones, termedH2A, H2B, H3 and H4 surrounded by 146 base pairs of DNA form thefundamental unit of chromatin, the nucleosome. The N-terminal tails ofthe core histones contain lysines that are sites forpost-transcriptional acetylation. Acetylation neutralizes the potentialof the side chain to form a positive charge on the lysine side chain,and is thought to impact chromatin structure.

Histone Deacetylases (HDACs) are zinc-containing enzymes which catalysethe removal of acetyl groups from the ε-amino termini of lysine residuesclustered near the amino terminus of nucleosomal histones. HDACs may bedivided into two classes, the first (HDAC 1, 2, 3 and 8) represented byyeast Rpd3-like proteins, and the second (HDAC 4, 5, 6, 7, 9 and 10)represented by yeast Hda1-like proteins. The reversible process ofacetylation is important in transcriptional regulation and cell-cycleprogression. HDAC deregulation has been associated with several cancersand HDAC inhibitors, such as Trichostatin A (a natural product isolatedfrom Streptomyces hygroscopicus), have been shown to exhibit significantanti-tumour effects and inhibition of cell-growth (Meinke, P. T.,Current Medicinal Chemistry, 8, 211-235 (2001)). Yoshida et al, Exper.Cell Res., 177, 122-131 (1988) teaches that Trichostatin A causes arrestof rat fibroblasts at the G1 and G2 phases of the cell cycle, therebyimplicating HDAC in cell cycle regulation. Furthermore, Trichostatin Ahas been shown to induce terminal differentiation, inhibit cell growth,and prevent the formation of tumours in mice (Finnin et al., Nature,401, 188-193 (1999)).

To date only a few inhibitors of HDAC are known in the art. There isthus a need to identify additional HDAC inhibitors.

Accordingly, the present invention provides a compound of the formula(I):

wherein:

-   -   Ring A is a heterocyclyl, wherein if said heterocyclyl contains        an —NH— moiety that nitrogen may be optionally substituted by a        group selected from K;    -   R¹ is a substituent on carbon and is selected from halo, nitro,        cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino,        carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl,        C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆)₂amino,        C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,        N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆-alkylS(O)_(a) wherein a is 0 to        2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,        N,N—(C₁₋₆alkyl)₂sulphamoyl, aryl, aryloxy, arylC₁₋₆alkyl,        heterocyclic group, (heterocyclic group)C₁₋₆alkyl, or a group        (B-E-); wherein R¹, including group (B-E-), may be optionally        substituted on carbon by one or more W; and wherein if said        heterocyclic group contains an —NH— moiety that nitrogen may be        optionally substituted by J;    -   W is halo, nitro, cyano, hydroxy, trifluoromethyl,        trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,        sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,        C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,        N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,        N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,        C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,        N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl, or a group        (B′-E′-); wherein W, including group (B′-E′-), may be optionally        substituted on carbon by one or more Y;    -   Y and Z are independently selected from halo, nitro, cyano,        hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,        carbamoyl, mercapto, sulphamoyl, C₁₋₆ alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,        N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,        N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,        C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,        N—(C₁₋₆alkyl)sulphamoyl or N,N—(C₁₋₆alkyl)₂sulphamoyl;    -   G, J and K are independently selected from C₁₋₈alkyl,        C₂₋₈alkenyl, C₁₋₈alkanoyl, C₁₋₈alkylsulphonyl,        C₁₋₈alkoxycarbonyl, carbamoyl, N—(C₁₋₈alkyl)carbamoyl,        N,N—(C₁₋₈alkyl)carbamoyl, benzyloxycarbonyl, benzoyl,        phenylsulphonyl, aryl, arylC₁₋₆alkyl or (heterocyclic        group)C₁₋₆alkyl; wherein G, J and K may be optionally        substituted on carbon by one or more Q; and wherein if said        heterocyclic group contains an —NH— moiety that nitrogen may be        optionally substituted by hydrogen or C₁₋₆alkyl;    -   Q is halo, nitro, cyano, hydroxy, trifluoromethyl,        trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,        sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl, C₁₋₆alkoxy,        C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,        N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,        N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,        C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,        C₁₋₆alkoxycarbonylamino, N—(C₁₋₆alkyl)sulphamoyl,        N,N—(C₁₋₆alkyl)₂sulphamoyl, aryl, aryloxy, aryl C₁₋₆alkyl,        arylC₁₋₆alkoxy, heterocyclic group, (heterocyclic        group)C₁₋₆alkyl, (heterocyclic group)C₁₋₆alkoxy, or a group        (B″-E″-); wherein Q, including group (B″-E″-), may be optionally        substituted on carbon by one or more Z;    -   B, B′ and B″ are independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkylC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic        group, (heterocyclic group)C₁₋₆alkyl, phenyl or        phenylC₁₋₆-alkyl; wherein B, B′ and B″ may be optionally        substituted on carbon by one or more D; and wherein if said        heterocyclic group contains an —NH— moiety that nitrogen may be        optionally substituted by a group selected from G;    -   E, E′ and E″ are independently selected from —N(R^(a))—, —O—,        —C(O)O—, —OC(O)—, —C(O)—, —N(R^(a))C(O)—,        —N(R^(a))C(O)N(R^(b))—, —N(R^(a))C(O)O—, —OC(O)N(R^(a))—,        —C(O)N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))—, —N(R^(a))SO₂—;        wherein R^(a) and R^(b) are independently selected from hydrogen        or C₁₋₆alkyl optionally substituted by one or more F and r is        0-2;    -   D and F are independently selected from halo, nitro, cyano,        hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,        carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,        N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,        N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,        C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,        N—(C₁₋₆alkyl)sulphamoyl or N,N—(C₁₋₆alkyl)₂sulphamoyl;    -   m is 0, 1, 2, 3 or 4; wherein the values of R¹ may be the same        or different;    -   R² is halo;    -   n is 0, 1 or 2; wherein the values of R² may be the same or        different;    -   R³ is amino or hydroxy;    -   R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl,        trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,        sulphamoyl, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkoxy,        C₁₋₃alkanoyl, C₁₋₃alkanoyloxy, N—(C₁₋₃alkyl)amino,        N,N—(C₁₋₃alkyl)₂amino, C₁₋₃alkanoylamino,        N—(C₁₋₃alkyl)carbamoyl, N,N—(C₁₋₃alkyl)₂carbamoyl,        C₁₋₃alkylS(O)_(a) wherein a is 0 to 2, C₁₋₃alkoxycarbonyl,        N—(C₁₋₃alkyl)sulphamoyl, N,N—(C₁₋₃alkyl)₂sulphamoyl;    -   p is 0, 1 or 2; wherein the values of R⁴ may be the same or        different;    -   or a pharmaceutically acceptable salt or in vivo hydrolysable        ester or amide thereof; with the proviso that said compound is        not    -   N-(2-amino-6-hydroxyphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;    -   N-(2-amino-6-methylphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;    -   N-(2-aminophenyl)-4-(1-t-butoxycarbonylhomopiperazin-4-yl)benzamide;        or    -   N-(2-aminophenyl)-4-(1-methylhomopiperazin-4-yl)benzamide.

According to a further aspect of the present invention, there isprovided a compound of the formula (I) wherein:

-   -   Ring A is a heterocyclyl;    -   R¹ is halo, nitro, cyano, hydroxy, trifluoromethyl,        trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,        sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,        C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,        N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,        N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,        C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,        N—(C₁₋₆alkyl)sulphamoyl, N,N—(C₁₋₆alkyl)₂sulphamoyl or a group        (B-E-); wherein,    -   B is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₈-cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl, phenyl, heterocyclyl,        phenylC₁₋₆alkyl or heterocyclylC₁₋₆alkyl; wherein B may be        optionally substituted on carbon by one or more D; and wherein        if said heterocyclyl contains an —NH— moiety that nitrogen may        be optionally substituted by a group selected from G;    -   E is —N(R^(a))—, —O—, —C(O)O—, —OC(O)—, —C(O)—, —N(R^(a))C(O)—,        —C(O)N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))—, —N(R^(a))SO₂—;        wherein R^(a) is hydrogen or C₁₋₆alkyl optionally substituted by        one or more D and r is 0-2;    -   D is independently selected from halo, nitro, cyano, hydroxy,        trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl,        mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,        N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,        N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl,        C₁₋₆alkylS(O)_(a) wherein a is 0 to 2, C₁₋₆alkoxycarbonyl,        N—(C₁₋₆alkyl)sulphamoyl and N,N—(C₁₋₆alkyl)₂sulphamoyl;    -   G is selected from C₁₋₄alkyl, C₁₋₄alkanoyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonyl, carbamoyl, N—(C₁₋₄alkyl)carbamoyl,        N,N—(C₁₋₄alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and        phenylsulphonyl;    -   m is 0, 1, 2, 3 or 4; wherein the values of R¹ may be the same        or different;    -   R² is halo;    -   n is 0, 1 or 2; wherein the values of R² may be the same or        different;    -   R³ is amino or hydroxy;    -   R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl,        trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,        sulphamoyl, C₁₋₃alkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₁₋₃alkoxy,        C₁₋₃alkanoyl, C₁₋₃alkanoyloxy, N—(C₁₋₃alkyl)amino,        N,N—(C₁₋₃alkyl)₂amino, C₁₋₃alkanoylamino,        N—(C₁₋₃alkyl)carbamoyl, N,N—(C₁₋₃alkyl)₂carbamoyl,        C₁₋₃alkylS(O)_(a) wherein a is 0 to 2, C₁₋₃alkoxycarbonyl,        N—(C₁₋₃alkyl)sulphamoyl, N,N—(C₁₋₃alkyl)₂sulphamoyl;    -   p is 0, 1 or 2; wherein the values of R⁴ may be the same or        different;    -   or a pharmaceutically acceptable salt or in vivo hydrolysable        ester or amide thereof; with the proviso that said compound is        not        N-(2-amino-6-hydroxyphenyl)-4-(1-methylhomopiperazin-4-yl)lbenzamide;        N-(2-amino-6-methylphenyl)-4-(1-methylhomopiperazin-4-yl)lbenzamide;        N-(2-aminophenyl)-4-(1-t-butoxycarbonylhomopiperazin-4-yl)lbenzamide;        or N-(2-aminophenyl)-4-(1-methylhomopiperazin-4-yl)lbenzamide.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups. For example, “C₁₋₈alkyl” and “C₁₋₆alkyl”includes methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, andt-butyl. However, references to individual alkyl groups such as ‘propyl’are specific for the straight-chained version only and references toindividual branched chain alkyl groups such as ‘isopropyl’ are specificfor the branched chain version only. The term “halo” refers to fluoro,chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 3-12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a ring sulphur atom maybe optionally oxidised to form the S-oxide(s). Preferably a“heterocyclyl” is a saturated, partially saturated or unsaturated,monocyclic ring containing 5 or 6 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen or a 8-10 membered bicyclic ringwhich may, unless otherwise specified, be carbon or nitrogen linked,wherein a ring sulphur atom may be optionally oxidised to formS-oxide(s). Examples and suitable values of the term “heterocyclyl” arethiazolidinyl, pyrrolidinyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl,2-azabicyclo[2.2.1]heptyl, morpholinyl, tetrahydrofuranyl, furanyl,tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl,1,3-dioxolanyl, homopiperazinyl, thienyl, pyrrolyl, pyrazolyl,oxadiazolyl, tetrazolyl, oxazolyl, thienopyrimidinyl, thienopyridinyl,thieno[3,2d]pyrimidinyl, 1,3,5-triazinyl, purinyl,1,2,3,4-tetrahydroquinolinyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, benzothienyl, benzofuranyl, indazolyl, quinazolinyl,cinnolinyl, phthalazinyl, quinoxalinyl, napthyridinyl, benzotriazolyl,pyrrolothienyl, imidazothienyl, isoxazolyl, imidazolyl, thiadiazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl,pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl,-quinolyl,quinazolinyl, and 1-isoquinolinyl.

A “heterocyclic group” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 3-12 atoms of which atleast one atom is chosen from nitrogen, sulphur or oxygen, which may,unless otherwise specified, be carbon or nitrogen linked, wherein a CH₂group can optionally be replaced by a C(O), and wherein a ring sulphuratom may be optionally oxidised to form the S-oxide(s). Preferably a“heterocyclic group” is a saturated, partially saturated or unsaturated,monocyclic ring containing 5 or 6 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen or a 9 or 10 membered bicyclicring which may, unless otherwise specified, be carbon or nitrogenlinked, wherein a CH₂ group can optionally be replaced by a C(O), andwherein a ring sulphur atom may be optionally oxidised to formS-oxide(s). Examples and suitable values of the term “heterocyclicgroup” are pyrrolidinyl, 2-pyrrolidonyl 2,5-dioxopyrrolidinyl,2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-triazolinyl, oxazolidinyl,2-oxazolidonyl, 5,6-dihydro-uracilyl, 1,3-benzodioxolyl,1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, morpholinyl,2-oxotetrahydrofuranyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,piperidinyl, piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl,1,3-dioxolanyl, homopiperazinyl, thiophenyl, thienopyridinyl,thienopyrimidinyl, thieno[3,2d]pyrimidinyl, 1,3,5-triazinyl, purinyl,quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,tetrahydroisoquinolinyl, imidazolyl, benzimidazolyl, benzothiazolyl,benzoxazolyl, benzothiophenyl, benzofuranyl, indazolyl, quinazolinyl,cinnolinyl, phthalazinyl, quinoxalinyl, napthyridinyl, oxazolyl,isoxazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl, isoindolyl,pyrimidinyl, thiazolyl, pyrazolyl, 3-pyrrolinyl, pyrazinyl, pyridazinyl,pyridinyl, pyridonyl, pyrimidonyl and 1-isoquinolinyl.

An “aryl” group is, for example, phenyl, indenyl, indanyl, naphthyl,tetrahydronaphthyl or fluorenyl, preferably phenyl.

An example of “C₁₋₆alkanoyloxy” is acetoxy. Examples of“C₁₋₈alkoxycarbonyl”, “C₁₋₆alkoxycarbonyl” and C₁₋₄alkoxycarbonylinclude methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.Examples of C₂₋₆alkynyl are ethynyl and 2-propynyl. Examples of“C₁₋₆alkoxy” include methoxy, ethoxy and propoxy. Examples of“C₁₋₆alkanoylamino” and C₁₋₃alkanoylamino include formamido, acetamidoand propionylamino. Examples of “C₁₋₆alkylS(O)_(a) wherein a is 0 to 2”include C₁₋₄alkylsulphonyl, C₁₋₃alkylS(O)_(a), methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of“C₁₋₈alkanoyl”, “C₁₋₆alkanoyl” and C₁₋₄alkanoyl include C₁₋₃alkanoyl,propionyl and acetyl. Examples of “N—C₁₋₆alkylamino” andN—(C₁₋₃alkyl)amino include methylamino and ethylamino. Examples of“N,N—(C₁₋₆alkyl)₂amino” and N,N—(C₁₋₂alkyl)₂amino includedi-N-methylamino, di-(N-ethyl)amino, di-(N-butyl)amino andN-ethyl-N-methylamino. Examples of “C₂₋₈alkenyl” are C₂₋₆alkenyl andC₂₋₃alkenyl, and include vinyl, allyl, and 1-propenyl. Examples of“N—(C₁₋₈alkyl)sulphamoyl” and“N—(C₁₋₆alkyl)sulphamoyl” areN—(C₁₋₃alkyl)sulphamoyl, N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.Examples of “N—(C₁₋₆alkyl)₂sulphamoyl” are N,N—(C₁₋₃alkyl)₂sulphamoyl,N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of“N—(C₁₋₈alkyl)carbamoyl” and “N—(C₁₋₆alkyl)carbamoyl” areN—(C₁₋₄alkyl)carbamoyl, N—(C₁₋₃alkyl)carbamoyl, methylaminocarbonyl, andethylaminocarbonyl. Examples of “N,N—(C₁₋₈alkyl)₂carbamoyl” and“N,N—(C₁₋₆alkyl)₂carbamoyl” are N,N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₂alkyl)₂carbamoyl, dimethylaminocarbonyl andmethylethylaminocarbonyl. Examples of “(heterocyclic group)C₁₋₆alkyl”include piperidin-1-ylmethyl, piperidin-1-ylethyl, piperdin-1-ylpropyl,pyridylmethyl, 3-morpholinopropyl, 2-morpholinoethyl and2-pyrimid-2-ylethyl. Examples of “(heterocyclic group)C₁₋₆-alkoxy”include (heterocyclic group)methoxy, (heterocyclic group)ethoxy and(heterocyclic group)propoxy. Examples of “arylC₁₋₆alkyl” include benzyl,2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl Examples of “aryloxy”include phenoxy and naphthyloxy. Examples of “C₃₋₈cycloalkyl” includecyclopropyl and cyclohexyl. Examples of “C₃₋₈cycloalkylC₁₋₆alkyl”include cyclopropylmethyl and 2-cyclohexylpropyl. Examples of“C₁₋₆alkoxycarbonylamino” include methoxycarbonylamino andt-butoxycarbonylamino.

Within this specification composite terms are used to describe groupscomprising more that one functionality such as arylC₁₋₆alkyl. Such termsare to be interpretted as is understood by a person skilled in the art.For example arylC₁₋₆alkyl comprises C₁₋₆alkyl substituted by aryl andsuch a group includes benzyl, 2-phenylethyl, 2-phenylpropyl and3-phenylpropyl.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for exampleacetic, hydrochloric, hydrobromic, sulphuric, phosphoric,trifluoroacetic, citric or maleic acid. In addition a suitablepharmaceutically acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmetetylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

The compounds of the formula (I) may be administered in the form of anin vivo hydrolysable ester or in vivo hydrolysable amide of a compoundof the formula (I).

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆-alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group-includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN—(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),N,N-dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an in vivo hydrolyzable amide of a compound of theformula (I) containing a carboxy group is, for example, a N—C₁₋₆alkyl orN,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess HDAC inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess HDAC inhibitory activity.

Further values of Ring A, R¹, R², R³, R⁴, m, n and p are as follows.Such values may be used where appropriate with any of the definitions,claims or embodiments defined hereinbefore or hereinafter.

Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl,piperidinyl, piperazinyl, pyradazinyl, pyrazinyl, thiazolyl, thienyl,thienopyrimidinyl, thienopyridinyl, purinyl, triazinyl, oxazolyl,pyrazolyl, or furanyl; wherein if Ring A contains an —NH— moiety thatnitrogen may be optionally substituted by a group selected from K.

Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl,pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl, morpholin-4-yl,piperidin-4-yl, piperidin-3-yl, piperdin-2-yl, piperazin-4-yl,pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl, thien-2-yl,thieno[3,2d]pyrimidinyl, thieno[3,2b]pyrimidinyl, thieno[3,2b]pyridinyl,purin-6-yl or triazin-6-yl; wherein if Ring A contains an —NH— moietythat nitrogen may be optionally substituted by a group selected from K.

Ring A is a pyridyl, quinolyl, pyrimidyl, morpholinyl, piperidinyl,piperazinyl, pyradazinyl, pyrazinyl, thiazyl or furanyl.

Ring A is a pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinoline-8-yl,pyradizin-2-yl, furan-3-yl, morpholinyl, thiazol-2-yl, pyrimidin-6-yl,piperidin-4-yl or piperazin-4-yl.

Ring A is pyridin-4-yl, pyridin-3-yl, quinoline-8-yl, piperidin-4-yl orpiperazin-4-yl.

R¹ is a substituent on carbon and is selected from halo, amino,C₁₋₆alkyl, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino, aryl, aryloxy, arylC₁₋₆alkyl,heterocyclic group, (heterocyclic group)C₁₋₆alkyl, or a group (B-E-);wherein R¹, including group (B-E-), may be optionally substituted oncarbon by one or more W; and wherein if said heterocyclic group containsan —NH— moiety that nitrogen may be optionally substituted by J;

W is hydroxy, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino ora group (B′-E′-); wherein W, including group (B′-E′-), may be optionallysubstituted on carbon by one or more Y;

Y and Z are independently selected from halo, nitro, cyano, hydroxy,C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino or C₁₋₆alkanoylamino;

G, J and K are independently selected from C₁₋₈alkyl, C₂₋₈ alkenyl,C₁₋₈alkanoyl, aryl, arylC₁₋₆alkyl or (heterocyclic group)C₁₋₆alkyl;wherein G, J and K may be optionally substituted on carbon by one ormore Q; and wherein if said heterocyclic group contains an —NH— moietythat nitrogen may be optionally substituted by hydrogen or C₁₋₆alkyl;

Q is cyano, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy, C₁₋₆alkoxycarbonyl,C₁₋₆alkoxycarbonylamino, aryl, aryloxy or a group (B″-E″-); wherein Q,including group (B″-E″-), maybe optionally substituted on carbon by oneor more Z;

B, B′ and B″ are independently selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl, aryl,arylC₁₋₆alkyl, heterocyclic group, (heterocyclic group)C₁₋₆alkyl, phenylor phenylC₁₋₆alkyl; wherein B, B′ and B″ may be optionally substitutedon carbon by one or more D; and wherein if said heterocyclic groupcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from G;

E, E′ and E″ are independently selected from —N(R^(a))—, —O—, —C(O)O—,—OC(O)—, —C(O)—, —N(R^(a))C(O)—, —N(R^(a))C(O)N(R^(b))—,—N(R^(a))C(O)O—, —OC(O)N(R^(a))—, —C(O)N(R^(a))—, —S(O)_(r)—,—SO₂N(R^(a))—, —N(R^(a))SO₂—; wherein R^(a) and R^(b) are independentlyselected from hydrogen or C₁₋₆alkyl optionally substituted by one ormore F and r is 0-2;

D and F are independently selected from halo, C₁₋₆alkoxy orN,N—(C₁₋₆alkyl)₂amino.

R¹ is a substituent on carbon and is selected from fluoro, chloro,amino, methyl, ethyl, propyl, methoxy, N-methylamino, N-ethylamino,N-propylamino, N-butylamino, phenyl, naphthylethyl, piperizin-1-yl,piperdin-1-yl, piperdin-4-yl, 2-(thiomethyl)-pyrimidin-4-yl,tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl,1,2,5-thiadiazol-3-ylethyl, piperdin-1-ylmethyl, pyridin-2-ylmethyl, ora group (B-E-); wherein R¹, including group (B-E-), may be optionallysubstituted on carbon by one or more W; and wherein if said heterocyclicgroup contains an —NH— moiety that nitrogen may be optionallysubstituted by J;

W is hydroxy, methyl, ethyl, ethoxy, N,N-(diethyl)amino,N,N-(dibutyl)amino, or a group (B′-E′-); wherein W, including group(B′-E′-), may be optionally substituted on carbon by one or more Y;

Y and Z are independently selected from fluoro, chloro, bromo, nitro,cyano hydroxy, methoxy, N,N-(dimethyl)amino or methylcarbonylamino;

G, J and K are independently selected from methyl, ethyl, propyl,pentyl, 2-methylbutyl, butyl, acetyl, benzyl, 3-(pyrrol-1-yl)propyl orpyrrolidin-2-one-(5S)-methyl; wherein G, J and K may be optionallysubstituted on carbon by one or more Q; and wherein if said heterocyclicgroup contains an —NH— moiety that nitrogen may be optionallysubstituted by hydrogen or methyl;

Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy,methoxycarbonyl, t-butoxycarbonlyamino, phenyl or a group (B″-E″-);wherein Q, including group (B″-E″-), may be optionally substituted oncarbon by one or more Z;

B, B′ and B″ are independently selected from methyl, ethyl, propyl,cyclohexyl, phenyl, benzyl, 1,2,3,4-tetrahydroquinolinyl,3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl,3-morpholinopropyl, 3-(4-methylpiperazin-1-yl)propyl,2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl orimidazol-1-ylpropyl; wherein B, B′ and B″ may be optionally substitutedon carbon by one or more D; and wherein if said heterocyclic groupcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from G;

E, E′ and E″ are independently selected from —N(R^(a))—, —O—, —C(O)—,—NHC(O)—, —N(R^(a))C(O)O—; wherein R^(a) is hydrogen or methyloptionally substituted by one or more F;

D and F are independently selected from fluoro, methoxy or ethoxy.

R¹ is fluoro, chloro, amino, methyl, methoxy,3-morpholin-4-ylpropylamino, (3-morpholin-4-yl)ethylamino, acetyl,benzyl, methoxycarbonylmethyl, 2-pyrrolidin-1-ylethoxy,3-morpholinopropoxy, N-(2-fluorophenyl)propanamide,4-(diethylamino)phenylcarbonylmethyl,3-(4-methylpiperazin-1-yl)propylamino, 2-piperidin-1-ylethylamino,2-[N,N-(diethyl)amino]ethylamino, pyridin-3-ylmethylamino,3-piperidin-1-ylpropylamino, imidazol-1-ylpropylamino,3-methoxypropylamino, 3-morpholinopropylamino, piperazin-1-yl,N-ethylamino, 4-methylpiperazin-1-yl, 1-(3-phenoxy)propyl,1-(3-cyanophenyl)methyl, 1-(4-cyanophenyl)methyl,tetrahydrofuran-2-ylmethyl, 1-(3-benzyloxy)propyl, 3-methoxybenzyl,2,3-dihydroxypropyl, 2-(methylcarbonyloxy)ethyl, 3-(pyrrol-1-yl)propyl,1-[3-(2-methoxyethoxy)]propyl, 2-(4-acetamidophenyoxy)ethyl,2-(t-butoxycarbonylamino)ethyl, 2-(t-butoxycarbonylamino)propyl,2-[(2-methoxyphenyl)oxy]ethyl, (1,2,3,4-tetrahydroquinolin-1-yl)acetyl,2-[N-(2-fluorophenyl)ylacetamide]ethyl, methoxycarbonylmethyl,2-(ethoxy)ethyl, 4-methylpent-3-enyl, tetrahydropyran-2-ylmethyl,1-(2S)-2-methylbutyl, 4-(benzyloxy)butyl, 2-[4-(nitro)phenoxy)]ethyl,2-[N,N-(dibutyl)amino]ethylamino,3-[(N-methyl-N-phenyl)amino]propylamino,N-3-[2-(dimethylamino)ethoxy]propylamino, 2-[4-(acetamido)phenoxy]ethyl,2-[4-(hydroxyphenoxy)]ethyl, 1,2,5-thiadiazol-3-ylethyl,piperdin-1-ylmethyl, 2-[4-(chloro)phenoxy]ethyl,pyrrolidin-2-one-(5S)-methyl, phenylaminocarbonyloxymethyl,cyclohexylaminocarbonyloxymethyl, 2-(thiomethyl)-pyrimidin-4-yl orpyridin-2-ylmethyl.

R¹ is halo, amino, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₃alkanoyloxy,N—(C₁₋₃alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₃alkanoylamino,N—(C₁₋₃alkyl)carbamoyl, N,N—(C₁₋₃alkyl)₂carbamoyl.

R¹ is halo, amino, C₁₋₆alkyl or C₁₋₆alkoxy.

R¹ is halo, amino, methyl or methoxy.

m is 0, 1, 2, 3 or 4; wherein the values of R¹ may be the same ordifferent.

m is 0, 1, or 2; wherein the values of R¹ may be the same or different.

m is 0 or 1.

m is 0.

m is 1.

R² is halo.

R² is fluoro or chloro.

R² is fluoro.

n is 0, 1 or 2, wherein the values of R² may be the same or different.

n is 0 or 1.

n is 0.

n is 1.

R³ is amino or hydroxy.

R³ is amino.

R³ is hydroxy.

R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,amino, carboxy or carbamoyl.

R⁴ is halo, cyano, trifluoromethyl or trifluoromethoxy.

R⁴ is halo.

p is 0, 1 or 2, wherein the values of R⁴ may be the same or different.

p is 0 or 1.

p is 0.

p is 1.

Therefore in an additional aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

-   -   Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl,        morpholinyl, piperidinyl, piperazinyl, pyradazinyl, pyrazinyl,        thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl,        triazinyl, oxazolyl, pyrazolyl, or furanyl; wherein if Ring A        contains an —NH— moiety that nitrogen may be optionally        substituted by a group selected from K;    -   R¹ is a substituent on carbon and is selected from halo, amino,        C₁₋₆alkyl, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino, aryl, aryloxy,        arylC₁₋₆alkyl, heterocyclic group, (heterocyclic        group)C₁₋₆alkyl, or a group (B-E-); wherein R¹, including group        (B-E-), may be optionally substituted on carbon by one or more        W; and wherein if said heterocyclic group contains an —NH—        moiety that nitrogen may be optionally substituted by J;    -   W is hydroxy, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy,        N,N—(C₁₋₆alkyl)₂amino or a group (B′-E′-); wherein W, including        group (B′-E′-), may be optionally substituted on carbon by one        or more Y;    -   Y and Z are independently selected from halo, nitro, cyano,        hydroxy, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino or C₁₋₆alkanoylamino;    -   G, J and K are independently selected from C₁₋₈alkyl,        C₂₋₈alkenyl, C₁₋₈alkanoyl, aryl, arylC₁₋₆alkyl or (heterocyclic        group)C₁₋₆alkyl; wherein G, J and K may be optionally        substituted on carbon by one or more Q; and wherein if said        heterocyclic group contains an —NH— moiety that nitrogen may be        optionally substituted by hydrogen or C₁₋₆alkyl;    -   Q is cyano, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy,        C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, aryl, aryloxy or a        group (B″-E″-); wherein Q, including group (B″-E″-), may be        optionally substituted on carbon by one or more Z;    -   B, B′ and B″ are independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,        C₃₋₈cycloalkylC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic        group, (heterocyclic group)C₁₋₆alkyl, phenyl or phenylC₁₋₆alkyl;        wherein B, B′ and B″ may be optionally substituted on carbon by        one or more D; and wherein if said heterocyclic group contains        an —NH— moiety that nitrogen may be optionally substituted by a        group selected from G;    -   E, E′ and E″ are independently selected from —N(R^(a))—, —O—,        —C(O)O—, —OC(O)—, —C(O)—, —N(R^(a))C(O)—,        —N(R^(a))C(O)N(R^(a))—, —N(R^(a))C(O)O—, —OC(O)N(R^(a))—,        —C(O)N(R^(a))—, S(O)_(r)—, —SO₂N(R^(a))—, —N(R^(a))SO₂—; wherein        R^(a) and R^(b) are independently selected from hydrogen or        C₁₋₆alkyl optionally substituted by one or more F and r is 0-2;    -   D and F are independently selected from halo, C₁₋₆alkoxy or        N,N—(C₁₋₆alkyl)₂amino;    -   m is 0, 1, 2, 3 or 4; wherein the values of R¹ may be the same        or different;    -   R² is fluoro or chloro;    -   n is 0, 1 or 2, wherein the values of R² may be the same or        different;    -   R³ is amino or hydroxy;    -   R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl,        trifluoromethoxy, amino, carboxy or carbamoyl;    -   p is 0, 1 or 2, wherein the values of R⁴ may be the same or        different;    -   or a pharmaceutically acceptable salt or in vivo hydrolysable        ester or amide thereof.

Therefore in an additional aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

-   -   Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl,        quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl,        morpholinyl, piperidin-4-yl, piperidin-3-yl, piperdin-2-yl,        piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl,        thien-2-yl, thieno[3,2d]pyrimidinyl, thieno[3,2b]pyrimidinyl,        thieno[3,2b]pyridinyl, purin-6-yl or triazin-6-yl; wherein if        Ring A contains an —NH— moiety that nitrogen may be optionally        substituted by a group selected from K;    -   R¹ is a substituent on carbon and is selected from fluoro,        chloro, amino, methyl, ethyl, propyl, methoxy, N-methylamino,        N-ethylamino, N-propylamino, N-butylamino, phenyl,        naphthylethyl, piperazin-1-yl, piperidin-1-yl, piperidin-4-yl,        2-(thiomethyl)-pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl,        tetrahydropyran-2-ylmethyl, 1,2,5-thiadiazol-3-ylethyl,        piperidin-1-ylmethyl, pyridin-2-ylmethyl, or a group (B-E-);        wherein R¹, including group (B-E-), may be optionally        substituted on carbon by one or more W; and wherein if said        heterocyclic group contains an —NH— moiety that nitrogen may be        optionally substituted by J;    -   W is hydroxy, methyl, ethyl, ethoxy, N,N-(diethyl)amino,        N,N-(dibutyl)amino, or a group (B′-E′-); wherein W, including        group (B′-E′-), may be optionally substituted on carbon by one        or more Y;    -   Y and Z are independently selected from fluoro, chloro, bromo,        nitro, cyano, hydroxy, methoxy, N,N-(dimethyl)amino or        methylcarbonylamino;    -   G, J and K are independently selected from methyl, ethyl,        propyl, pentyl, 2-methylbutyl, butyl, acetyl, benzyl,        3-(pyrrol-1-yl)propyl or pyrrolidin-2-one-(5S)-methyl; wherein        G, J and K may be optionally substituted on carbon by one or        more Q; and wherein if said heterocyclic group contains an —NH—        moiety that nitrogen may be optionally substituted by hydrogen        or methyl;    -   Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy,        methoxycarbonyl, t-butoxycarbonylamino, phenyl or a group        (B″-E″-); wherein Q, including group (B″-E″-), may be optionally        substituted on carbon by one or more Z;    -   B, B′ and B″ are independently selected from methyl, ethyl,        propyl, cyclohexyl, phenyl, benzyl,        1,2,3,4-tetrahydroquinolinyl, 3-morpholinopropyl,        2-morpholinoethyl, 2-pyrrolidin-1-ylethyl, 3-morpholinopropyl,        3-(4-methylpiperazin-1-yl)propyl, 2-piperidin-1-ylethyl,        3-piperidin-1-ylpropyl, pyridin-3-ylmethyl or        imidazol-1-ylpropyl; wherein B, B′ and B″ may be optionally        substituted on carbon by one or more D; and wherein if said        heterocyclic group contains an —NH— moiety that nitrogen may be        optionally substituted by a group selected from G;    -   E, E′ and E″ are independently selected from —N(R^(a))—, —O—,        —C(O)—, —NHC(O)—, —N(R^(a))C(O)O—; wherein R^(a) is hydrogen or        methyl optionally substituted by one or more F;    -   D and F are independently selected from fluoro, methoxy or        ethoxy;    -   m is 0, 1, or 2; wherein the values of R¹ may be the same or        different;    -   R² is fluoro;    -   n is 0 or 1;    -   R³ is amino;    -   R⁴ is halo;    -   p is 0, 1 or 2, wherein the values of R⁴ may be the same or        different;    -   or a pharmaceutically acceptable salt or in vivo hydrolysable        ester or amide thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the Examples, or a pharmaceutically acceptable salt or anin vivo hydrolysable ester or amide thereof.

In another aspect of the invention there is provided a compound of theformula (I) or a or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt or an invivo hydrolysable ester thereof which process (wherein Ring A, R¹, R²,R³, R⁴, m, n and p are, unless otherwise specified, as defined informula (I)) comprises of:

-   -   (a) The reaction of a compound of the formula (II)        wherein X is a reactive group, with a compound of the formula        (III)        wherein L¹ and L² are ligands;    -   (b) The reaction of a compound of the formula (IV)        wherein L¹ and L² are ligands, with a compound of the formula        (V)        wherein X is a reactive group; or    -   (c) The reaction, in the presence of        4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium        chloride, of a compound of the formula (VI)        with a compound of the formula (VII)        and thereafter if necessary:    -   i) converting a compound of the formula (I) into another        compound of the formula (I); and/or    -   ii) removing any protecting groups.

A suitable base for process (a), (b) or (c) is, for example, an organicamine base such as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali oralkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide, or, for example, an alkali metal hydride, forexample sodium hydride, or a metal alkoxide such as sodium ethoxide.

A suitable reactive group X is, for example, a halo, alkoxy, aryloxy orsulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy,methanesulphonyloxy, trifluromethanesulphonyloxy ortoluene-4-sulphonyloxy group. The reactions are conveniently carried outin the presence of a suitable inert solvent or diluent, for example analkanol or ester such as methanol, ethanol, isopropanol or ethylacetate, a halogenated solvent such as methylene chloride, chloroform orcarbon tetrachloride, an ether such as tetrahydrofuran,1,2-dimethoxyethane or 1,4-dioxan, an aromatic solvent such as toluene,or a dipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.The reactions are conveniently carried out at a temperature in therange, for example, 10 to 250° C., preferably in the range 40 to 80° C.;

A suitable value for the ligands L¹ and L² which are present on theboron atom include, for example, a hydroxy, (1-4C)alkoxy or (1-6C)alkylligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy,butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand. Alternativelythe ligands L¹ and L² may be linked such that, together with the boronatom to which they are attached, they form a ring. For example, L¹ andL² together may define an oxy-(2-4C)alkylene-oxy group, for example anoxyethyleneoxy or oxytrimethyleneoxy group such that, together with theboron atom to which they are attached, they form a cyclic boronic acidester group;

A suitable catalyst for process (a) or (b) includes, for example, ametallic catalyst such as a palladium(0), palladium(II), nickel(0) ornickel(II) catalyst, for exampletetrakis(triphenylphosphine)palladium(0), palladium(II) chloride,palladium(II) bromide, bis(triphenylphosphine)palladium(II) chloride,tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II)bromide or bis(triphenylphosphine)nickel(II) chloride. In addition afree radical initiator may conveniently be added, for example an azocompound such as azo(bisisobutyronitrile);

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halo group. Particular examples ofmodifications include the reduction of a nitro group to an amino groupby for example, catalytic hydrogenation with a nickel catalyst ortreatment with iron in the presence of hydrochloric acid with heating;oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for ex)ample a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Biological Assays

The following assays can be used to measure the effects of the compoundsof the present invention as HDAC inhibitors, as inhibitors in vitro ofpooled histone deacetylases from nuclear extracts prepared from thehuman cervical cancer cell line HeLa, as inhibitors in vitro ofrecombinant human HDAC1 produced in Hi5 insect cells, and as inducers invitro of Histone H3 acetylation in whole cells.

(a) In Vitro Enzyme Assay of Pooled Histone Deacetylases

HDAC inhibitors were screened against pooled histone deacetylases fromnuclear extracts prepared from the human cervical cancer cell line HeLa.

The deacetylase assays were carried out in a 40 μl reaction. 2.5 μg ofnuclear extract diluted in 15 μl of reaction buffer (25 mM TrisHCl (pH8), 137 mM NaCl, 2.7 mM KCl,1 mM MgCl₂) was mixed with either bufferalone (5 μl ) or buffer containing compound (5 μl) for 30 minutes atambient temperature. 25 μM fluor-de-lys substrate (Biomol) diluted in 20μl of buffer was then added to the reaction and incubated for one hourat ambient temperature. The reaction was stopped by addition of an equalvolume (40 μl) fluor de lys developer (Biomol) containing Trichostatin Aat 2 μM. The reaction was allowed to develop for 30 minutes at ambienttemperature and then fluorescence measured at an excitation wavelengthof 360 nM and an emission wavelength of 465 nM. IC₅₀ values for HDACenzyme inhibitors were determined by performing dose response curveswith individual compounds and determining the concentration of inhibitorproducing fifty percent decrease in the maximal signal (no inhibitorcontrol).

(b) In Vitro Enzyme Assay of Recombinant HDAC1

HDAC inhibitors were screened against recombinant human HDAC1 producedin Hi5 insect cells. The enzyme was cloned with a FLAG tag at theC-terminal of the gene and affinty purified using Anti-FLAG M2 agarosefrom SIGMA (A2220).

The deacetylase assays were carried out in a 50 μl reaction. 75 ng ofenzyme diluted in 15 μl of reaction buffer (25 mM TrisHCl (pH 8), 137 mMNaCl, 2.7 mM KCl,1 mM MgCl₂) was mixed with either buffer alone (5 μl)or buffer containing compound (10 μl) for 30 minutes at ambienttemperature. 50 μM fluor-de-lys substrate (Biomol) diluted in 25 μl ofbuffer was then added to the reaction and incubated for one hour atambient temperature. The reaction was stopped by addition of an equalvolume (50 μl) fluor de lys developer (Biomol) containing Trichostatin Aat 2 μM. The reaction was allowed to develop for 30 minutes at ambienttemperature and then fluorescence measured at an excitation wavelengthof 360 nM and an emission wavelength of 465 nM. IC₅₀ values for HDACenzyme inhibitors were determined by performing dose response curveswith individual compounds and determining the concentration of inhibitorproducing fifty percent decrease in the maximal signal (no inhibitorcontrol).

(c) In Vitro Enzyme Assay of Histone Deacetylase Activity in Whole Cells

Histone H3 acetylation in whole cells using immunohistochemistry andanalysis using the Cellomics arrayscan. A549 cells were seeded in 96well plates at 1×10⁴ cells/well, and allowed to adhere overnight. Theywere treated with inhibitors for 24 hours and then fixed in 1.8%formaldehyde in tris buffered saline (TBS) for one hour. Cells werepermeabilized with ice-cold methanol for 5 minutes, rinsed in TBS andthen blocked in TBS 3% low-fat dried milk for 90 minutes. Cells werethen incubated with polyclonal antibodies specific for the acetylatedhistone H3 (Upstate #06-599) diluted 1 in 500 in TBS 3% milk for onehour. Cells were rinsed three times in TBS and then incubated withfluorescein conjugated secondary antibodies (Molecular Probes #A11008) &Hoechst 333542 (1 μg/ml) (Molecular Probes #H3570) in TBS 1% Bovineserum albumin (Sigma #B6917) for one hour. Unbound antibody was removedby three rinses with TBS and after the final rinse 100 μl of TBS wasadded to the cells and the plates sealed and analysed using theCellomics arrayscan.

EC₅₀ values for HDAC inhibitors were determined by performing doseresponse curves with individual compounds and then determining theconcentration of inhibitor producing fifty percent of the maximal signal(reference compound control—Trichostatin A (Sigma)).

Although the pharmacological properties of the compounds of the formula(I) vary with structural change as expected, in general activitypossessed by compounds of the Formula I, may be demonstrated at thefollowing concentrations or doses in one or more of the above tests (a)and (b):

-   -   Test (a):—IC₅₀ in the range, for example, <50.0 μM;    -   Test (b):—IC₅₀ in the range, for example, <2.5 μM;    -   Test (c):—EC₅₀ in the range, for example, <9.0 μM;

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula(I), or a pharmaceutically acceptable salt or in vivo hydrolysable esteror amide thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0.1-100 mg/kg, andthis normally provides a therapeutically-effective dose. A unit doseform such as a tablet or capsule will usually contain, for example 1-250mg of active ingredient. Preferably a daily dose in the range of 1-50mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt or in vivo hydrolysable ester or amidethereof, are effective cell cycle inhibitors (anti-cell proliferationagents), which property is believed to arise from their HDAC inhibitoryproperties. We also believe that the compounds of the present inventionmay be involved in the inhibition of angiogenesis, activation ofapoptosis and differentiation. Accordingly the compounds of the presentinvention are expected to be useful in the treatment of diseases ormedical conditions mediated alone or in part by HDAC enzymes, i.e. thecompounds may be used to produce a HDAC inhibitory effect in awarm-blooded animal in need of such treatment. Thus the compounds of thepresent invention provide a method for treating the proliferation ofmalignant cells characterised by inhibition of HDAC enzymes, i.e. thecompounds may be used to produce an anti-proliferative effect mediatedalone or in part by the inhibition of HDACs.

According to one aspect of the present invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester or amide thereof, as defined hereinbefore foruse in a method of treatment of the human or animal body by therapy.

Thus according to a further aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester or amide thereof, as defined hereinbefore foruse as a medicament.

According to a further aspect of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltor in vivo hydrolysable ester or amide thereof, as defined hereinbeforein the manufacture of a medicament for use in the production of a HDACinhibitory effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing a HDAC inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof the formula (I), or a pharmaceutically acceptable salt or in vivohydrolysable ester or amide thereof, as defined hereinbefore.

According to a further aspect of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltor in vivo hydrolysable ester or amide thereof, as defined hereinbeforein the manufacture of a medicament for use in the production of a cellcycle inhibitory (anti-cell-proliferation) effect in a warm-bloodedanimal such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing a cell cycle inhibitory(anti-cell-proliferation) effect in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester or amidethereof, as defined hereinbefore.

According to an additional feature of this aspect of the invention thereis provided a method of treating cancer in a warm-blooded animal, suchas man, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester or amidethereof, as defined hereinbefore.

According to a further feature of the invention there is 74a compound ofthe formula (I), or a pharmaceutically acceptable salt or in vivohydrolysable ester or amide thereof, as defined hereinbefore in themanufacture of a medicament for use in the treatment of cancer.

According to an additional feature of this aspect of the invention thereis provided a compound of the formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester or amide thereof, asdefined hereinbefore, for use in the treatment of cancer.

In a further aspect of the present invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltor in vivo hydrolysable ester or amide thereof, as defined hereinbefore,in the manufacture of a medicament for use in lung cancer, colorectalcancer, breast cancer, prostate cancer, lymphoma and leukaemia.

In a further aspect of the present invention the is provided a method oftreating lung cancer, colorectal cancer, breast cancer, prostate cancer,lymphoma or leukaemia, in a warm-blooded animal, such as man, in need ofsuch treatment which comprises administering to said animal an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester or amide thereof, asdefined hereinbefore.

Cancers that are amenable to treatment with the present inventioninclude oesophageal cancer, myeloma, hepatocellular, pancreatic andcervical cancer, Ewings tumour, neuroblastoma, kaposis sarcoma, ovariancancer, breast cancer, colorectal cancer, prostate cancer, bladdercancer, melanoma, lung cancer [including non small cell lung cancer(NSCLC) and small cell lung cancer (SCLC)], gastric cancer, head andneck cancer, brain cancer, renal cancer, lymphoma and leukaemia.

There is further provided is a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester or amidethereof, as defined hereinbefore, for use in a method of treatinginflammatory diseases, autoimmune diseases and allergic/atopic diseases.

In particular a compound of the formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester or amide thereof, asdefined hereinbefore, is provided for use in a method of treatinginflammation of the joint (especially rheumatoid arthritis,osteoarthritis and gout), inflammation of the gastro-intestinal tract(especially inflammatory bowel disease, ulcerative colitis andgastritis), inflammation of the skin (especially psoriasis, eczema,dermatitis), multiple sclerosis, atherosclerosis, spondyloarthropathies(ankylosing spondylitis, psoriatic arthritis, arthritis connected toulcerative colitis), AIDS-related neuropathies, systemic lupuserythematosus, asthma, chronic obstructive lung diseases, bronchitis,pleuritis, adult respiratory distress syndrome, sepsis, and acute andchronic hepatitis (either viral, bacterial or toxic).

Further provided is a compound of the formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester or amide thereof, asdefined hereinbefore, for use as a medicament in the treatment ofinflammatory diseases, autoimmune diseases and allergic/atopic diseasesin a warm-blooded animal such as man.

In particular a compound of the formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester or amide thereof, asdefined hereinbefore, is provided for use as a medicament in thetreatment of inflammation of the joint (especially rheumatoid arthritis,osteoarthritis and gout), inflammation of the gastrointestinal tract(especially inflammatory bowel disease, ulcerative colitis andgastritis), inflammation of the skin (especially psoriasis, eczema,dermatitis), multiple sclerosis, atherosclerosis, spondyloarthropathies(ankylosing spondylitis, psoriatic arthritis, arthritis connected toulcerative colitis), AIDS-related neuropathies, systemic lupuserythematosus, asthma, chronic obstructive lung diseases, bronchitis,pleuritis, adult respiratory distress syndrome, sepsis, and acute andchronic hepatitis (either viral, bacterial or toxic).

Further provided is the use of a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester or amidethereof, as defined hereinbefore, in the manufacture of a medicament foruse in the treatment of inflammatory diseases, autoimmune diseases andallergic/atopic diseases in a warm-blooded animal such as man.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular cell-proliferation disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged.

The HDAC inhibitory activity defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. In thefield of medical oncology it is normal practice to use a combination ofdifferent forms of treatment to treat each patient with cancer. Inmedical oncology the other component(s) of such conjoint treatment inaddition to the cell cycle inhibitory treatment defined hereinbefore maybe: surgery, radiotherapy or chemotherapy. Such chemotherapy may includeone or more of the following categories of anti-tumour agents:

-   -   (i) other cell cycle inhibitory agents that work by the same or        different mechanisms from those defined hereinbefore, for        example cyclin dependent kinase (CDK) inhibitors, in particular        CDK2 inhibitors;    -   (ii) cytostatic agents such as antioestrogens (for example        tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene),        progestogens (for example megestrol acetate), aromatase        inhibitors (for example anastrozole, letrazole, vorazole,        exemestane), antiprogestogens, antiandrogens (for example        flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH        agonists and antagonists (for example goserelin acetate,        luprolide), inhibitors of testosterone 5α-dihydroreductase (for        example finasteride), anti-invasion agents (for example        metalloproteinase inhibitors like marimastat and inhibitors of        urokinase plasminogen activator receptor function) and        inhibitors of growth factor function, (such growth factors        include for example vascular endothelial growth factor,        epithelial growth factor, platelet derived growth factor and        hepatocyte growth factor such inhibitors include growth factor        antibodies, growth factor receptor antibodies, tyrosine kinase        inhibitors and serine/threonine kinase inhibitors);    -   (iii) antiproliferative/antineoplastic drugs and combinations        thereof, as used in medical oncology, such as antimetabolites        (for example antifolates like methotrexate, fluoropyrimidines        like 5-fluorouracil, purine and adenosine analogues, cytosine        arabinoside); antitumour antibiotics (for example anthracyclines        like doxorubicin, daunomycin, epirubicin and idarubicin,        mitomycin-C, dactinomycin, mithramycin); platinum derivatives        (for example cisplatin, carboplatin); alkylating agents (for        example nitrogen mustard, melphalan, chlorambucil, busulphan,        cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);        antimitotic agents (for example vinca alkaloids like        vincrisitine and taxoids like taxol, taxotere); topoisomerase        inhibitors (for example epipodophyllotoxins like etoposide and        teniposide, amsacrine, topotecan);    -   (iv) antiangiogenic agents that work by different mechanisms        from those defined hereinbefore (for example receptor tyrosine        kinases like Tie-2, inhibitors of integrin αvβ3 function,        angiostatin, razoxin, thalidomide), and including vascular        targeting agents; and    -   (v) differentiation agents (for example retinoic acid and        vitamin D).

According to this aspect of the invention there is provided apharmaceutical product comprising a compound of the formula (I) asdefined hereinbefore and an additional anti-tumour substance as definedhereinbefore for the conjoint treatment of cancer.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts or in vivohydrolysable esters or amides thereof, are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof cell cycle activity in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

For the benefit of the reader, where a pharmaceutical compositioncomprising a compound of formula (I), or the use of a compound offormula (I) as a medicament, or the use of a compound of formula (I) ina method of treatment, or the use of a compound of formula (I) in themanufacture of a medicament, or the use of a compound of formula (I) inthe treatment of cancer, is described herein, it is to be understoodthat here, the definition of the compound of formula (I) includes thecompoundsN-(2-amino-6-hydroxyphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;N-(2-amino-6-methylphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;N-(2-aminophenyl)-4-(1-t-butoxycarbonylhomopiperazin-4-yl)benzamide; andN-(2-aminophenyl)-4-(1-methylhomopiperazin-4-yl)benzamide.

The invention will now be illustrated in the following Examples inwhich, generally:

-   -   (i) operations were carried out at ambient temperature, i.e. in        the range 17 to 25° C. and under an atmosphere of an inert gas        such as argon unless otherwise stated;    -   (ii) evaporations were carried out by rotary evaporation in        vacuo and work-up procedures were carried out after removal of        residual solids by filtration;    -   (iii) column chromatography (by the flash procedure) and medium        pressure liquid chromatography (MPLC) were performed on Merck        Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18        (Art. 9303) reversed-phase silica obtained from E. Merck,        Darmstadt, Germany or high pressure liquid chromatography (HPLC)        was performed on C18 reverse phase silica, for example on a        Dynamax C-18 60 Å preparative reversed-phase column;    -   (iv) yields, where present, are not necessarily the maximum        attainable;    -   (v) in general, the structures of the end-products of the        Formula (I) were confirmed by nuclear magnetic resonance (NMR)        and/or mass spectral techniques; fast-atom bombardment (FAB)        mass spectral data were obtained using a Platform spectrometer        and, where appropriate, either positive ion data or negative ion        data were collected; NMR chemical shift values were measured on        the delta scale [proton magnetic resonance spectra were        determined using a Jeol JNM EX 400 spectrometer operating at a        field strength of 400 MHz, Varian Gemini 2000 spectrometer        operating at a field strength of 300 MHz or a Bruker AM300        spectrometer operating at a field strength of 300 MHz]; the        following abbreviations have been used: s, singlet; d, doublet;        t, triplet; q, quartet; m, multiplet; br, broad;    -   (vi) intermediates were not generally fully characterised and        purity was assessed by thin layer chromatographic, HPLC,        infra-red (IR) and/or NMR analysis;    -   (vii) melting points are uncorrected and were determined using a        Mettler SP62 automatic melting point apparatus or an oil-bath        apparatus; melting points for the end-products of the        formula (I) were determined after crystallisation from a        conventional organic solvent such as ethanol, methanol, acetone,        ether or hexane, alone or in admixture;    -   (viii) the following abbreviations have been used:        -   DMF N+EE, N-dimethylformamide        -   DMSO dimethylsulphoxide        -   THF tetrahydrofuran

EXAMPLE 1 N-(2-Aminophenyl)-4-pyridin-4-ylbenzamide

N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-4-ylbenzamide (Method 1; 100mg, 0.26 mmol), 1,4-dioxane (2 ml) and a 4M solution of hydrogenchloride in dioxane (2 ml) were stirred at ambient temperature forapproximately 20 hours. The resultant precipitate was collected byfiltration and washed with iso-hexane and diethyl ether and dried invacuo to give the title compound as its hydrochloride (43 mg, 46%); NMRSpectrum: (DMSO-d₆) 7.31 (m, 2H), 7.39 (t, 1H), 7.54 (t, 1H), 8.17 (d,2H), 8.30 (d, 2H), 8.40 (d, 2H), 8.96 (d, 2H), 10.62 (s, 1H); MassSpectrum: M+H⁺ 290.

EXAMPLE 2

Using an analogous procedure to that described in Example 1, theappropriate N-(2-t-butoxycarbonylaminophenyl)-benzamide startingmaterial was reacted to give the compounds described in Table 1. Unlessotherwise stated, each compound was obtained as its hydrochloride salt.TABLE 1

Note R¹ Analytical Data SM 1 quinolin-8-yl NMR Spectrum:(DMSO-d₆)7.37(t, Meth 1H), 7.49(t, 1H), 7.62(d, 1H), 2 7.78(m, 5H),7.93(d, 1H), 8.18(d, 1H), 8.31(d, 2H), 8.72(d, 1H), 9.04(dd, 1H),10.75(s, 1H); Mass Spectrum: M + H⁺ 340. 2 pyridin-3-yl NMR Spectrum:(DMSO-d₆) Meth 7.32(m, 2H), 7.43(d, 1H), 7.57(d, 3 1H), 7.95(dd, 1H),8.03(d, 2H), 8.27(d, 2H), 8.72(d, 1H), 8.83(d, 1H), 9.25(s, 1H),10.60(s, 1H); Mass Spectrum: M + H⁺ 290. 3 pyridin-2-yl NMR Spectrum:(DMSO-d₆): Meth Formic acid salt 6.63(t, 1H), 6.80(d, 1H), 6.98(t, 41H), 7.23(d, 1H), 7.44(t, 1H), 7.95(t, 1H), 8.13(m, 3H), 8.22(d, 2H),8.72(d, 1H), 9.74(s, 1H); Mass Spectrum: M + H⁺ 290. 46-(methoxy)-1,2-pyra- NMR Spectrum: (DMSO-d₆) Meth zin-3-yl 4.09(s, 3H),7.32(m, 4H), 7.49(m, 5 1H), 8.24(m, 5H), 10.46(s, 1H); Mass Spectrum:M + H⁺ 321. 5 furan-3-yl NMR Spectrum: (DMSO-d₆) Meth 7.09(s, 1H),7.25(m, 3H), 7.58(d, 6 1H), 7.83(d, 3H), 8.06(d, 2H), 8.33(s, 1H),10.32(s, 1H); Mass Spectrum: M + H⁺ 279. 6 2-methylyridin-4-yl NMRSpectrum: (DMSO-d₆) Meth 2.82(s, 3H), 7.21(m, 1H), 7.29(m, 7 2H),7.51(d, 2H), 8.20(d, 2H), 8.31(m, 3H), 8.41(s, 1H), 8.89(d, 1H),10.51(s, 1H); Mass Spectrum: M + H⁺ 304. 7 2-fluoropyridin-4-yl NMRSpectrum: (DMSO-d₆) Meth 7.26-7.33(m, 3H), 7.49(d, 1H), 8 7.68(s, 1H),7.83(m, 1H), 8.08(d, 2H), 8.23(d, 2H), 8.37(d, 1H), 10.50(s, 1H); MassSpectrum: M + H⁺ 308. 8 thiazol-2-yl NMR Spectrum: (DMSO-d₆)7.39(t, Meth1H), 7.48(t, 1H), 7.56(d, 1H), 9 7.64(d, 1H), 7.92(d, 1H), 8.02(d, 1H),8.13(d, 2H), 8.27(d, 2H), 10.77(s, 1H); Mass Spectrum: M + H⁺ 296. 92-amino-pyri- NMR Spectrum: (DMSO-d₆) Meth midin-6-yl 7.32(m, 2H),7.41(m, 1H), 7.57(m, 10 2H), 8.30(m, 4H), 8.51(d, 1H), 10.64(s, 1H);Mass Spectrum: M + H⁺ 306. 10 pyrimidin-6-yl NMR Spectrum: (DMSO-d₆)Meth 7.33(m, 3H), 7.52(m, 1H), 8.25(m, 11 3H), 8.40(d, 2H), 8.95(d, 1H),9.33(s, 1H), 10.52(s, 1H); Mass Spectrum: M + H⁺ 291. 11 2-chloro-pyri-NMR Spectrum: (DMSO-d₆) Meth midin-6-yl 7.39(m, 2H), 7.46(dd, 1H), 127.58(dd, 1H), 8.30(m, 3H), 8.39(d, 2H), 8.93(d, 1H), 10.72(s, 1H); MassSpectrum: M + H⁺ 325.

EXAMPLE 3 N-(2-Aminophenyl)-4-morpholinobenzamide

A solution of 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17; 104mg, 0.5 mmol) in DMF (1.6 ml) was added to 4-morpholinobenzoic acid (149mg, 0.5 mmol) followed by4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride(Method 18, 138 mg, 0.5 mmol) and the reaction mixture stirred atambient temperature for 48 hours. The solvent was removed in vacuo andthe resultant residue partitioned between ethyl acetate and water. Theorganic phase was separated, then washed with water, brine and driedover sodium sulfate then filtered. The organic extracts wereconcentrated by half and a 4M solution of hydrogen chloride in1,4-dioxane (1 ml) added. The reaction mixture was stirred at ambienttemperature for a further 64 hours and the resultant precipitate wascollected by filtration. This solid was purified by preparative masstriggered HPLC, eluting with an increasing gradient of acetonitrile inwater (which contains 5% (v/v) of a 1% (v/v) solution of formic acid inmethanol) to afford the title compound (17 mg, 12%); NMR Spectrum:(DMSO-d₆) 3.25 (m, 4H),3.76 (m, 4H), 4.83 (s, 2H), 6.60 (m, 1H), 6.79(dd, 1H), 6.96 (m, 1H), 7.01 (d, 2H), 7.16 (dd, 1H), 7.90 (d, 2H), 9.31(brs, 1H); Mass Spectrum: M+H⁺ 298.

EXAMPLE 4 N-(2-Aminophenyl)-4-(1-methylpiperidin-4-yl)benzamide

N-(2-Aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 48 mg, 0.16mmol) was stirred and dissolved in anhydrous DMF (2 ml) at ambienttemperature. Potassium carbonate (23 mg, 0.16 mmol) was added followedby iodomethane (0.01 ml, 0.16 mmol) and the mixture stirred for 3 hours.The reaction mixture was diluted with water (20 ml) and extracted withethyl acetate. The combined extracts were washed once with brine, driedover magnesium sulfate, filtered and the solvent evaporated to give thetitle compound as a colourless solid (16 mg, 32%); NMR Spectrum:(DMSO-d₆) 1.70 (m, 4H), 1.96 (m, 2H), 2.18 (s, 3H), 2.85 (m, 2H), 3.03(m, 1H), 4.84 (b, 2H), 6.57 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16(d, 1H), 7.36 (d, 2H), 7.99 (d, 2H), 9.54 (b, 1H); Mass Spectrum: M+H⁺310.

EXAMPLE 5 N-(2-Aminophenyl)-4-piperidin-4-ylbenzamide

A 4M solution of hydrogen chloride in dioxane (5 ml, 20 mmol) was addedto a stirred solution ofN-(2-t-butoxycarbonylaminophenyl)-4-(1-t-butoxycarbonylpiperidin-4-yl)benzamideMethod 15, 693 mg, 1.40 mmol) in 1,4-dioxane (5 ml) and the mixturestirred at ambient temperature for 18 hours. The resultant precipitatewas filtered and washed with diethyl ether. The resultant solid wasdissolved in water and basified to pH 12 with 2M solution of aqueoussodium hydroxide. The resultant precipitate was filtered, washed withwater and dried in vacuo to give the title compound (338 mg, 82%); NMRSpectrum: DMSO-d₆) 1.52 (m, 2H), 1.69 (m, 2H), 2.60 (m, 3H), 3.02 (m,2H), 4.84 (br, 2H), 6.58 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d,1H), 7.34 (d, 2H), 7.89 (d, 2H), 9.53 (br, 1H); Mass Spectrum: M+H⁺ 296.

EXAMPLE 6 N-(2-Aminophenyl)-4-(1-methylpiperazin-4-yl)benzamide

N-(2-t-Butoxycarbonylaminophenyl)-4-(1-methylpiperazin-4-yl)benzamide(Method 16, 196 mg, 0.48 mmol) was dissolved in a 1M solution ofhydrogen chloride in diethyl ether (7.2 ml, 7.2 mmol) and stirred atambient temperature for 24 hours. The resultant precipitate wascollected by filtration and washed with diethyl ether. To the solid wasadded a 2M solution of aqueous sodium hydroxide (5 ml) and the mixtureextracted with ethyl acetate. The organic extract was dried overmagnesium sulfate, filtered and evaporated to afford the title compoundas a colourless solid (16 mg, 11%); NMR Spectrum: (CDCl₃) 2.36 (s, 3H),2.57 (t, 4H), 3.33 (t, 4H), 3.88 (br, 2H), 6.81 (m, 2H), 6.91 (d, 2H)7.06 (t, 1H), 7.27 (d, 1H), 7.79 (s, 1H), 7.80 (m, 2H); Mass Spectrum:M+H⁺ 311.

EXAMPLE 7N-(2-Aminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamide

N-(2-Aminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamidetrihydrochloride (Method 19, 28 mg, 0.052 mmol) was dissolved in water(2 ml) and basified to pH 10 by the of addition of 28% aqueous ammoniumhydroxide solution (2 drops). The resultant precipitate was collected byfiltration and dried under vacuum at 40° C. overnight to afford thetitle compound as a yellow solid (9 mg, 40%); NMR (DMSO-d₆): 1.75 (m,2H), 2.37 (m, 6H), 3.41 (brm, 2H), 3.59 (m, 4H), 4.92 (s, 2H), 6.62 (t,1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.21 (m, 2H), 7.28 (t, 1H), 8.11 (d,2H), 8.22 (d, 2H), 8.39 (d, 1H), 9.74 (s, 1H); Mass Spectrum: M+H⁺ 433.

EXAMPLE 8N-(2-Aminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benzamide

N-(2-Aminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benzamidetrihydrochloride (Method 24, 22 mg, 0.042 mmol) was reacted in ananalogous manner to that described for Example 7 to afford the titlecompound as a pale yellow solid (12 mg, 68%); NMR (DMSO-d₆): 2.45 (m,4H), 2.54 (m, 2H), 3.51 (m, 2H), 3.59 (m, 4H), 4.92 (s, 2H), 6.62 (t,1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.07 (t, 1H), 7.20 (d, 1H), 7.24 (d,1H), 8.11 (d, 2H), 8.23 (d, 2H), 8.40 (d, 1H), 9.74 (s, 1H); MassSpectrum: M+H⁺ 419.

EXAMPLE 9

Using an analogous procedure to that described in Example 1, theappropriate N-(2-t-butoxycarbonylaminophenyl)benzamide starting materialwas reacted to give the compounds described in Table 2. Unless otherwisestated, each compound was obtained as its hydrochloride salt. TABLE 2

Note R¹ Analytical Data SM 1

NMR Spectrum: (DMSO-d₆) 1.39(m, 1H), 1.70(m, 1H), 1.79(m, 4H), 2.06(m,2H), 2.85(m, 2H), 3.12(m, 2H), 3.52(m, 2H), 4.41(d, 2H), 7.33(m, 2H),7.41(m, 2H), 7.59(m, 1H), 8.27(d, 2H), 8.32(d, 2H), 8.48(d, 1H),10.10(s, 1H), 10.61(s, 1H); Mass Spectrum: M + H⁺ 431. Meth 29 2

NMR Spectrum: (DMSO-d₆) 2.17(qn, 2H), 3.42(m, 2H), 4.33(t, 2H), 7.30(m,2H), 7.37(m, 2H), 7.57(m, 1H), 7.75(brm, 2H), 7.85(t, 1H), 8.26(s, 4H),8.45(d, 1H), 9.21(s, 1H), 10.56(s, 1H); Mass Spectrum: M + H⁺ 414. Meth30 3

NMR Spectrum: (DMSO-d₆) 2.08(m, 2H), 2.84(s, 3H), 3.28(m, 2H), 3.49(brm,6H), 3.69(brm, 4H), 7.32(m, 2H), 7.40(m, 2H), 7.57(m, 1H), 7.74(brm,1H), 8.26(d, 2H), 8.32(m, 2H), 8.47(d, 1H), 10.58(s, 1H); Mass Spectrum:M + H⁺446. Meth 31 4

NMR Spectrum: (DMSO-d₆) 1.22(t, 6H), 1.69(m, 2H), 1.77(m, 2H), 3.08(m,6H), 3.50(m, 2H), 7.33(m, 2H), 7.44(m, 2H), 7.60(m, 1H), 7.98(brs, 1H),8.30(m, 4H), 8.48(d, 1H), 10.12(s, 1H), 10.64(s, 1H); Mass Spectrum: M +H⁺433. Meth 32 5

NMR Spectrum: (DMSO-d₆) 1.25(t, 6H), 3.22(qn, 4H), 3.30(q, 2H),3.80(brm, 2H), 7.32(m, 2H), 7.40(m, 2H), 7.56(m, 1H), 7.61(brs, 1H),8.25(d, 2H), 8.32(d, 2H), 8.50(d, 1H), 10.14(brs, 1H), 10.57(s, 1H);Mass Spectrum: M + H⁺ 405. Meth 33 6

NMR Spectrum: (DMSO-d₆) 4.82(s, 2H), 7.35(m, 2H), 7.41(d, 1H), 7.45(m,1H), 7.59(m, 1H), 8.02(dd, 1H), 8.19(brs, 1H), 8.42(s, 4H), 8.48(m, 1H),8.58(m, 1H), 8.81(d, 1H), 8.92 (s, 1H), 10.62(s, 1H); Mass Spectrum: M +H⁺ 397. Meth 34 7

NMR Spectrum: (DMSO-d₆) 1.41(m, 1H), 1.73(m, 1H), 1.80(m, 4H), 2.95(m,2H), 3.30(m, 2H), 3.54(m, 2H), 3.81(m, 2H), 7.30(m, 2H), 7.35(m, 1H),7.40(d, 1H), 7.53(d, 1H), 7.63(brs, 1H), 8.24(d, 2H), 8.31(d, 2H),8.49(d, 1H), 9.93(brs, 1H), 10.51(s, 1H); Mass Spectrum: M + H⁺ 417.Meth 35 8

NMR Spectrum: (DMSO-d₆) 1.86(qn, 2H), 3.26(s, 3H), 3.45(t, 2H),3.50(brm, 2H), 7.32(m, 2H), 7.39(m, 2H), 7.54(m, 1H), 8.24(d, 2H),8.33(d, 2H), 8.47(d, 1H), 10.56(s, 1H); Mass Spectrum: M + H⁺378. Meth36 9

NMR Spectrum: (DMSO-d₆) 2.25(m, 2H)3.08(m, 2H), 3.27(m, 2H), 3.45(d,2H), 3.85(t, 2H), 3.97(m, 2H), 4.43(t, 2H), 7.24(s, 1H), 7.36(t, 1H),7.43(t, 1H), 7.44(d, 1H), 7.51(d, 1H), 7.62(d, 1H), 7.98(d, 2H), 8.27(d,2H), 8.29(d, 1H), 10.67(s, 1H), 11.26(s, 1H); Mass Spectrum: M + H⁺ 433.Meth 37 10

NMR Spectrum: (DMSO-d₆) 2.76(s, 3H), 7.28(m, 3H), 7.51(d, 1H), 7.93(d,1H), 8.05(d, 2H), 8.27(d, 2H), 8.75(d, 1H), 9.17(s, 1H), 10.46(s, 1H);Mass Spectrum: M + H⁺ 304. Meth 38 11

NMR Spectrum: (DMSO-d₆) 1.36(m, 1H), 1.78-1.66(m, 5H)2.05(m, 2H),2.86(q, 2H), 3.13(m, 2H), 3.57(m, 4H), 7.36(m, 4H), 7.53(d, 1H), 8.23(d,2H), 8.32(d, 2H), 8.37(d, 1H), 9.78(brs, 1H)10.59(s, 1H); Mass Spectrum:M + H⁺487. Meth 39 12

NMR Spectrum: (DMSO-d₆) 7.39(t, 1H), 7.45(t, 1H), 7.51(d, 1H), 7.63(d,1H), 7.80(d, 1H), 8.34(d, 2H), 8.39(d, 2H), 8.65(d, 1H), 9.35(s, 1H),10.77(s, 1H); Mass Spectrum: M + H⁺ 347. Meth 40 13

NMR Spectrum(DMSO-d₆): 1.39(m, 1H), 1.70(m, 1H), 1.78(m, 4H), 2.02(m,2H), 2.86(m, 2H), 3.08(m, 2H), 3.42(m, 4H), 7.37(m, 2H), 7.48(d, 1H),7.61(d, 1H), 7.86(d, 2H), 8.21(d, 2H), 8.81(s, 2H), 10.17(s, 1H),10.56(s, 1H); Mass Spectrum: M + H⁺431. Meth 41 14

NMR Spectrum(DMSO-d₆): 2.03(m, 2H), 2.82(t, 3H), 3.23(t, 2H), 3.45(m,6H), 3.67(m, 4H), 7.34(t, 1H), 7.42(t, 1H), 7.50(d, 1H), 7.62(d, 1H),7.85(d, 2H), 8.21(d, 2H), 8.81(s, 2H), 10.60(s, 1H); Mass Spectrum: M +H⁺ 446. Meth 42 15

NMR Spectrum(DMSO-d₆): 2.00(m, 2H), 3.08(m, 2H), 3.18(m, 2H), 3.43(m,4H), 3.87(m, 2H), 4.00(m, 2H), 7.34(m, 2H), 7.42(d, 1H)7.58(d, 1H),7.87(d, 2H), 8.19(d, 2H), 8.82(s, 2H), 10.46(s, 1H), 10.82(s, 1H); MassSpectrum: M + H⁺ 433. Meth 43 16

NMR Spectrum(DMSO-d₆): 1.91(m, 2H), 2.05(m, 2H), 3.13(m, 2H), 3.68(m,4H), 4.75(t, 2H), 7.36(m, 2H), 7.47(d, 1H), 7.60(d, 1H), 8.00(d, 2H),8.26(d, 2H), 9.11(s, 2H), 10.60(s, 1H), 10.80(s, 1H); Mass Spectrum: M +H⁺ 404. Meth 45 17

NMR Spectrum: 2.10(m, 2H), 3.06(m, 2H), 3.21(M, 2H), 3.43(d, 2H),3.55(m, 2H), 3.84(m, 2H), 3.94(m, 2H), 7.37(m, 2H), 7.42(m, 1H), 7.51(d,1H), 7.64(d, 1H), 8.23(d, 2H), 8.37(d 2H), 8.40(d, 1H), 10.75(s, 1H),11.10(brs, 1H); Mass Spectrum: M + H⁺ 489. Meth 65 18

NMR Spectrum: (DMSO-d₆) 1.41(m, 1H), 1.72(m, 1H), 1.80(m, 4H), 2.96(m,2H), 3.32(q, 2H), 3.57(m, 2H), 3.83(m, 2H), 7.34(m, 2H), 7.38(d, 1H),7.41(m, 1H), 7.58(m, 1H), 8.25(d, 2H), 8.35(d, 2H), 8.39(d, 1H), 9.92(s,1H), 10.63(s, 1H); Mass Spectrum: M + H⁺ 474. Meth 66 19

NMR Spectrum: (DMSO-d₆): 1.20(m, 5H), 1.54(d, 1H), 1.69(d, 2H), 1.78(d,2H), 3.30(m, 1H), 5.28(s, 2H), 7.29(d, 1H), 7.38(t, 1H), 7.44(t, 1H),7.52(d, 1H), 7.62(d, 1H), 8.00(s, 1H), 8.10(d, 2H), 8.25(d, 2H),10.66(s, 1H); Mass Spectrum: M + H⁺ 451. Meth 67 20

NMR Spectrum: (DMSO-d₆): 2.59(s, 3H), 4.93(s, 2H), 6.62(t, 1H), 6.81(d,1H), 7.01(t, 1H), 7.20(d, 1H), 7.75(d, 1H), 7.84(d, 1H), 7.94(d, 2H),8.08(d, 2H), 8.15(d, 1H), 8.65(d, 1H), 9.75(s, 1H); Mass Spectrum: M +H⁺ 419 Meth 68 21

NMR Spectrum: (DMSO-d₆) 7.34(t, 1H), 7.44(t, 1H), 7.60(d, 1H), 7.70(d,1H), 7.96(m, 2H), 8.10(d, 2H), 8.44(d, 2H), 8.67(m, 1H), 9.08(m, 1H),10.88(s, 1H); Mass Spectrum: M + H⁺ 346. Meth 74 22

NMR Spectrum: (DMSO-d₆) 7.37(m, 1H), 7.43(t, 1H), 7.49(dd, 1H), 7.61(dd,1H), 7.76(d, 1H), 8.11(d, 1H), 8.17(d, 2H), 8.33(d, 2H), 9.21(s, 1H),10.73(s, 1H); Mass Spectrum: M + H⁺ 347. Meth 75

EXAMPLE 10

Using an analogous procedure to that described in Example 1, theappropriate N-(2-t-butoxycarbonylaminophenyl)benzamide starting materialwas reacted to give the compounds described in Table 3. Unless otherwisestated, each compound was obtained as its hydrochloride salt. TABLE 3

1 3-pyridyl NMR Spectrum: (DMSO-d₆): 7.40(m, Meth 44 2H), 7.50(d, 1H),7.63(d, 1H), 7.91(t, 1H), 7.99(t, 1H), 8.18(m, 2H), 8.58(d, 1H), 8.89(d,1H), 9.10(s, 1H), 10.76(s, 1H); Mass Spectrum: M + H⁺ 308.

EXAMPLE 11

Using an analogous procedure to that described in Example 7, theappropriate N-(2-aminophenyl)-benzamide hydrochloride salt startingmaterial was reacted to give the compounds described in Table 4. Unlessotherwise stated, each compound was obtained as its free base. TABLE 4

Note R¹ Analytical Data SM 1

NMR Spectrum: (DMSO-d₆)1.74(m, 2H), 2.42(brm, 4H), 3.34(m, 4H), 3.60(m,4H), 4.91(s, 2H), 6.62(t, 2H), 6.81(m, 3H), 6.99(t, 1H), 7.20(d, 1H),7.79(d, 2H), 8.09(m, 3H), 9.72(s, 1H); Mass Spectrum: M + H⁺ 432. Meth46 2

NMR Spectrum: (DMSO-d₆)3.92(s, 3H), 5.00(brs, 2H), 6.63(t, 1H), 6.82(d,1H), 7.01(m, 1H), 7.23(d, 1H), 8.20(d, 2H), 8.70(s, 1H), 8.98(d, 2H),9.06(s, 1H), 9.82(s, 1H); Mass Spectrum: M + H⁺ 345. Meth 47 3

NMR Spectrum: (DMSO-d₆)2.84(m, 4H), 3.61(m, 4H), 4.62(s, 2H), 6.62(t,1H), 6.80(d, 1H), 6.99(t, 1H), 7.21(d, 1H), 8.09(d, 2H), 8.21(d, 2H),8.31(s, 1H), 8.53(s, 1H), 9.72(s, 1H); Mass Spectrum: M + H⁺ 375. Meth48 4

NMR Spectrum: (DMSO-d₆ @ 373K) 1.22(t, 6H)3.43(qn, 4H), 4.72(brs, 2H),6.65(t, 1H), 6.83(d, 1H), 6.90(m, 2H), 7.01(t, 1H), 7.28(d, 1H), 8.06(d,2H), 8.39(d, 2H), 9.44(s, 1H); Mass Spectrum:M + H⁺ 378. Meth 49 5

NMR Spectrum: (DMSO-d₆)2.26(s, 3H), 2.43(m, 4H), 3.86(m, 4H), 4.92(s,2H), 6.62(t, 1H), 6.81(d, 1H), 6.99(t, 1H), 7.20(d, 1H), 7.31(d, 1H),8.11(d, 2H), 8.26(d, 2H), 8.50(d, 1H), 9.75(s, 1H); Mass Spectrum: M +H⁺ 389. Meth 50

EXAMPLE 12N-(2-aminophenyl)-4-[5-(piperidin-1-ylmethyl)-1,3-thiazol-2-yl]benzamide

N-(2-t-butoxycarbonylaminophenyl)-4-[5-(piperidin-1-ylmethyl)-1,3-thiazol-2-yl]benzamide(Method 51, 271 mg, 0.54 mmol) was suspended in 1,4 dioxane (4 ml) and a4M solution of hydrogen chloride in 1,4-dioxane (4 ml) added. Thereaction mixture was stirred at ambient temperature for 17 hours. Theresultant precipitate was collected by filtration, washed with diethylether and air dried to yield the title compound as its hydrochloridesalt. The crude solid was purified using an Oasis MCX column, elutingwith methanol/dichloromethane (0-100%) then 2M ammonia inmethanol/methanol (0-20%) to give the tide compound as its free base(119 mg, 56%); NMR Spectrum: (DMSO-d₆) 1.40 (m, 2H), 1.50 (m, 4H), 2.41(m, 4H), 3.74 (s, 2H), 4.94 (s, 2H), 6.61 (t, 1H), 6.80 (d, 1H), 6.99(t, 1H), 7.18 (d, 1H), 7.80 (s, 1H), 8.06 (d, 2H), 8.09 (d, 2H), 9.78(s, 1H); Mass Spectrum: M+H⁺ 402.

EXAMPLE 13N-(2-aminophenyl)-4-[2-({3-[2-(dimethylamino)ethoxy]propyl}amino)pyrimidin-4-yl]benzamide

To a solution of dimethylaminoethoxypropylamine (2.02 mg, 12.5 μmol) inN,N-dimethylacetamide (125 μl), was added a solution ofN-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide (Method62, 2.2 mg, 5 μmol) in N,N-dimethylacetamide (100 μl). The reactionmixture was heated to 50° C. and agitated for a period of 16 hours,before being evaporated to dryness to give the title compound; MassSpectrum: M+H⁺ 435.

EXAMPLE 14

Using an analogous procedure to that described in Example 13,N-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide (Method62) was reacted with the appropriate amine to give the compoundsdescribed in Table 5. TABLE 5

Note R¹ Analytical Data SM 1

Mass Spectrum: M + H⁺ 453. CAS 53485-07-7 2

Mass Spectrum: M + H⁺ 461. CAS 3529-09-7

EXAMPLE 15

Using an analogous procedure to that described in Example 5, theappropriate N-(2-aminophenyl)benzamide hydrochloride salt startingmaterial was reacted to give the compounds described in Table 6. Unlessotherwise stated, each compound was obtained as its free base. TABLE 6

Note R¹ Analytical Data SM 1

NMR Spectrum: (DMSO-d₆): 4.93(s, 2H), 5.46(s, 2H), 6.62(t, 1H), 6.80(d,1H), 7.01(m, 2H), 7.21(d, 1H), 7.32(m, 2H), 7.50(d, 2H), 8.10(m, 5H),9.78(s, 1H), 9.83(s, 1H); Mass Spectrum: M + H⁺ 445 Meth 70

EXAMPLE 16 N-(2-aminophenyl)-4-piperazin-1-ylbenzamide

To a solution of 4-(4-t-butoxycarbonylpiperazin-1-yl)benzoic acid (1.0g, 3.3 mmol) and 1-(t-butoxycarbonylamino)-2-aminobenzene (Method 17,0.68 g, 3.3 mmol) in DMF (10 ml) was added4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride(1.1 g, 4.0 mmol) (Method 18). The mixture was stirred at ambienttemperature for 20 hours. The mixture was concentrated in vacuo and theresidue partitioned between water and ethyl acetate. The organic phasewas separated and the aqueous reextracted with ethyl acetate. Thecombined organic extracts were dried over magnesium sulfate andevaporated. The residue was purified by flash chromatography (elutingwith 4:1-1:1 isohexane/ethyl acetate). The product was dissolved in1,4-dioxane (2.5 ml) and treated with a 4M solution of hydrogen chloridein 1,4-dioxane (2.5 ml). The mixture was stirred at ambient temperaturefor 4 hours. The resulting solid was collected by filtration, tratedwith a 2M aqueous solution of sodium hydroxide and extracted with ethylacetate. The organic extract was dried over magnesium sulfate to affordthe title compound as a colourless solid (176 mg, 92%); NMR Spectrum:(DMSO-d₆) 2.89 (t, 4H), 3.25 (t, 4H), 4.90 (s, 2H), 6.66 (t, 1H), 6.84(d, 1H), 7.01 (m, 3H), 7.21 (d, 1H), 7.92 (d, 2H), 9.48 (s, 1H); MassSpectrum: M+H⁺ 297.

EXAMPLE 17 (RS)—N-(2-aminophenyl)-4-piperidin-3-ylbenzamide

To a solution ofN-(2-t-butoxycarbonylaminophenyl)-4-pyridin-3-ylbenzamide (2.0 g, 5.1mmol) (Method 3) in ethanol (20 ml) was added PtO₂ (200 mg) and theresulting mixture was heated at 80° C. under an atmosphere of hydrogenat 80 Bar for 16 hours. The mixture was allowed to cool and was filteredand evaporated to afford(RS)—N-(2-t-butoxycarbonylaminophenyl)-4-piperidin-3-ylbenzamide (1.9 g,94%).

To a solution of(RS)—N-(2-t-butoxycarbonylaminophenyl)-4-piperidin-3-ylbenzamide (1.0 g,2.5 mmol) in 1,4-dioxane (9.5 ml) was added a solution of hydrogenchloride (4M in 1,4-dioxane, 9.5 ml, 38 mmol) and the mixture stirred atambient temperature for 6 hours. The solid formed was collected byfiltration, washed with diethyl ether and dried in vacuo. It was treatedwith a 2M solution of aqueous sodium hydroxide and extracted three timeswith ethyl acetate. The combined organic extracts were dried overmagnesium sulfate and evaporated to afford the product as a colourlesssolid (0.73 g, 99%); NMR Spectrum: (DMSO-d₆) 1.71 (m, 4H), 2.61 (m, 2H),2.75 (m, 1H), 3.03 (m, 2H), 4.92(s, 2H), 6.65 (t, 1H), 6.83 (d, 1H),7.02 (t, 1H), 7.23 (d, 1H), 7.42 (d, 2H), 7.96 (d, 2H), 9.61 (s, 1H);Mass Spectrum: M+H⁺ 296.

EXAMPLE 18 N-(2-aminophenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamidedihydrochloride

t-Butyl4-{4-[({2-[(t-butoxycarbonyl)amino]phenyl}amino)carbonyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate(Method 71, 62 mg, 0.13 mmol) was stirred and dissolved in 1,4-dioxane(0.4 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (0.4 ml)added. The reaction mixture was stirred at ambient temperature for 24hours. The resultant precipitate was collected by filtration, washedwith diethyl ether and dried in vacuo at 60° C. to yield the titlecompound as an off white solid (34 mg, 89%); NMR Spectrum: (DMSO-d₆)2.70 (m, 2H), 3.30 (m, 2H), 3.76 (m, 2H), 6.33 (m, 1H), 7.23 (m, 2H),7.33 (m, 1H), 7.49 (m, 1H), 7.61 (d, 2H), 8.10 (d, 2H), 9.27 (s, 1H);Mass Spectrum: M+H⁺ 294.

EXAMPLE 19N-(2-aminophenyl)-4-(1-{3-[(2-fluorophenyl)amino]-3-oxopropyl}piperidin-4-yl)benzamide

N-(2-aminophenyl)-4-piperidine-4-ylbenzamide (Example 5, 162 mg, 0.55mmol), potassium carbonate (153 mg, 1.1 mmol) and(2-fluorophenyl)-3-bromopropionamide (149 mg, 0.61 mmol) in DMF (5 ml)were stirred at ambient temperature for approximately 20 hours. Themixture was concentrated in vacuo and the residue partitioned betweenwater and ethyl acetate. The organic layer was separated, dried overmagnesium sulfate and evaporated. The residue was purified by flashchromatography (eluting with 0-25% methanol/dichloromethane to affordthe product as a colourless solid (76 mg, 30%); NMR Spectrum: (CDCl₃)1.92 (m, 4H), 2.18 (m, 1H), 2.57 (t, 2H), 2.64 (m, 2H) 2.72 (t, 2H),3.19 (d, 2H), 3.62 (s, 2H), 6.80 (m, 2H), 7.05 (m, 4H), 7.31 (d, 1H),7.34 (d, 2H), 7.87 (d, 2H), 8.08 (s, 1H), 8.44 (t, 1H), 11.39 (s, 1H);Mass Spectrum: M+H⁺ 461.

EXAMPLE 20 4-(1-acetylpiperidin-4-yl)-N-(2-aminophenyl)benzamide

N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 30 mg, 0.10mmol) was stirred and dissolved in N,N-dimethylacetamide (2 ml) andacetic anhydride (0.011 ml, 0.11 mmol) added. The reaction was stirredat ambient temperature for 1 hour and then partitioned between water andethyl acetate. The organic layer was separated, washed with brine anddried over magnesium sulfate, filtered and evaporated to give the titlecompound as a colourless solid (23 mg, 68%); NMR Spectrum: (DMSO-d₆)1.48 (m, 1H), 1.64 (m, 1H), 1.79 (m, 2H), 2.02 (s, 3H), 2.59 (m, 1H),2.84 (m, 1H, 3.13 (m, 1H), 3.92 (d, 1H), 4.53 (d, 1H), 4.85 (s, 2H),6.58 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.15 (d, 1H), 7.37 (d, 2H),7.90 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H⁺ 338.

EXAMPLE 21

Using an analogous procedure to that described in Example 19,N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5) was reacted togive the compounds described in Table 7. TABLE 7

Note R¹ Analytical Data SM 1

NMR Spectrum: (DMSO-d₆) 1.39(s, 9H), 1.59(m, 2H), 1.71(m, 2H), 1.78(m,2H), 2.02(m, 2H), 2.34(m, 2H), 2.61(m, 1H), 2.98(m, 4H), 4.87(s, 2H),6.60(t, 1H), 6.78(d, 1H), 6.83(s, 1H), 6.97(t, 1H), 7.17(d, 1H), 7.38(d,2H), 7.91(d, 2H), 9.56(s, 1H); Mass Spectrum: M + H⁺ 453. 2

NMR Spectrum: (DMSO-d₆) 1.73(m, 4H), 2.07(m, 2H), 2.53(m, 1H), 2.92(m,2H), 3.51(s, 2H), 4.85(s, 2H), 6.56(t, 1H), 6.76(d, 1H), 6.95(t, 1H),7.15(d, 1H), 7.31(m, 7H), 7.89(d, 2H), 9.53(s, 1H); Mass Spectrum: M +H⁺ 386. 3

NMR Spectrum: (DMSO-d₆) 1.73(m, 4H), 2.37(m, 7H), 2.98(t, 2H), 3.30(m,2H), 3.71(m, 1H), 4.88(s, 2H), 6.60(t, 1H), 6.78(d, 1H), 6.97(t, 1H),7.16(d, 1H), 7.38(d, 2H), 7.55(s, 1H), 7.91(d, 2H), 9.58(s, 1H); MassSpectrum: M + H⁺ 393. 4

NMR Spectrum: (DMSO-d₆) 1.73(m, 4H), 2.18(t, 2H), 2.59(m, 1H), 2.75(t,2H), 3.09(d, 2H), 3.76(s, 3H), 4.09(t, 2H), 4.89(s, 2H), 6.60(t, 1H),6.79(d, 1H), 6.89(m, 2H), 6.99(m, 3H), 7.18(d, 1H), 7.39(d, 2H), 7.92(d,2H), 9.60(s, 1H); Mass Spectrum: M + H⁺ 446. 5

NMR Spectrum: (CDCl₃)1.88(m, 4H), 2.29(m, 2H), 2.62(m, 1H), 2.90(t, 2H),3.18(m, 2H), 3.89(s, 2H), 4.18(t, 2H), 6.86(m, 2H), 6.96(m, 3H), 7.11(t,1H), 7.31(m, 5H), 7.86(d, 2H), 7.90(s, 1H); Mass Spectrum: M + H⁺ 416. 6

NMR Spectrum: (DMSO-d₆) 1.73(m, 4H), 2.00(s, 3H), 2.16(t, 2H), 2.46(m,1H), 2.72(t, 2H), 3.07(m, 2H), 4.06(t, 2H), 4.89(s, 2H), 6.59(t, 1H),6.78(d, 1H), 6.89(d, 2H), 6.96(t, 1H), 7.17(d, 1H), 7.39(d, 2H), 7.47(d,2H), 7.91(d, 2H), 9.58(s, 1H), 9.77(s, 1H); Mass Spectrum: M + H⁺ 473.CAS no #57011-90-2 Justus Liebigs Ann. Chem. 1899, 287. DE 85988 7

NMR Spectrum: (DMSO-d₆) 1.61(m, 2H), 1.74(m, 2H), 2.20(t, 2H), 2.67(m,1H), 2.73(t, 2H), 2.92(m, 2H), 3.27(m, 2H), 3.34(s, 2H), 3.75(t, 2H),4.86(s, 2H), 6.60(t, 1H), 6.78(d, 1H), 6.97(t, 1H), 7.09(t, 1H), 7.18(m,3H), 7.35(d, 2H), 7.60(m, 1H), 7.91(d, 2H), 9.55(s, 1H); Mass Spectrum:M + H⁺ 470. Method 73 8

NMR Spectrum: (DMSO-d₆) 1.73(m, 4H), 2.16(m, 2H), 2.60(m, 1H), 2.74(t,2H), 3.07(m, 2H), 4.10(t, 2H), 4.88(s, 2H), 6.60(t, 1H), 6.78(d, 1H),6.98(m, 3H), 7.17(d, 1H), 7.33(d, 2H), 7.39(d, 2H), 7.91(d, 2H), 9.56(s,1H); Mass Spectrum: M + H⁺ 450. 9

NMR Spectrum: (DMSO-d₆) 1.75(m, 4H), 2.18(m, 2H), 2.61(m, 1H), 2.96(m,2H), 4.86(s, 2H), 6.60(t, 1H), 6.79(d, 1H), 6.97(t, 1H), 7.18(d, 1H),7.27(t, 1H), 7.39(d, 2H), 7.48(d, 1H), 7.78(t, 1H), 7.92(d, 2H), 8.50(d,1H), 9.56(s, 1H); Mass Spectrum: M + H⁺388. 10

Mass Spectrum: M + H⁺ 411 11

Mass Spectrum: M + H⁺ 411 12

Mass Spectrum: M + H⁺ 416 13

Mass Spectrum: M + H⁺ 439 14

Mass Spectrum: M + H⁺ 412 15

Mass Spectrum: M + H⁺ 370 16

Mass Spectrum: M + H⁺ 380 17

Mass Spectrum: M + H⁺ 444 18

Mass Spectrum: M + H⁺ 403 19

Mass Spectrum: M + H⁺ 382

EXAMPLE 22N-(2-aminophenyl)-4-[1-(4-bromobenzoyl)piperidin-4-yl]benzamide

To a solution of 4-bromobenzoic acid (1.0 g, 3.3 mmol) in DMF (5 ml) wasadded benzotriazolyloxytripyrollidinophosphonium hexafluorophosphate (99mg, 0.19 mmol) and the mixture stirred at ambient temperature for 30minutes. N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 50 mg,0.17 mmol) was added and the mixture stirred for a further 24 hours. Theresulting solution was absorbed onto an SCX-2 column, washed withmethanol (2 column volumes) and eluted with a 2M solution of ammonia inmethanol (2 column volumes) to afford the product. This was purified byflash chromatography (eluting with 0-20% methanol/dichloromethane) toafford the title compound as a colourless solid (29 mg, 18%); NMRSpectrum: (DMSO-d₆) 1.70 (m, 4H), 2.60 (m, 1H), 2.91 (m, 2H), 3.31 (m,2H), 4.89 (s, 2H), 6.60 (t, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.16 (d,1H), 7.43 (d, 4H), 7.67 (d, 2H), 7.93 (d, 2H), 9.60 (s, 1H); MassSpectrum: M+H⁺ 478.

EXAMPLE 23

Using an analogous procedure to that described in Example 19,(RS)—N-(2-aminophenyl)-4-piperidin-3-ylbenzamide was reacted to give thecompounds described in Table 8. TABLE 8

Note R¹ Analytical Data SM 1

NMR Spectrum: (DMSO-d₆) 1.47(m, 1H), 1.66(m, 2H), 1.85(m, 1H), 2.30(m,2H), 2.88(m, 3H), 3.29(m, 1H), 3.62(s, 3H), 4.87(s, 2H), 6.61(t, 1H),6.79(d, 1H), 6.98(t, 1H), 7.18(d, 1H), 7.40(d, 2H), 7.92(d, 2H), 9.57(s,1H); Mass Spectrum: M + H⁺ 368. 2

NMR Spectrum: (CDCl₃)1.42(m, 1H), 1.88(m, 3H), 2.39(m, 3H), 2.93(m, 4H),3.67 and 3.99(m, 1H), 3.80(m, 2H), 6.78(m, 2H), 7.02(t, 1H), 7.28(m,3H), 7.72(s, 2H), 7.77(d, 2H); Mass Spectrum: M + H⁺380. 3

NMR Spectrum: (DMSO-d₆) 1.48(m, 2H), 1.68(m, 1H), 1.80(m, 1H), 1.90(t,2H), 2.15(t, 1H), 2.22(t, 1H), 2.72(m, 2H), 2.82(m, 1H), 2.90(s, 2H),3.73(m, 2H), 4.86(s, 2H), 6.60(t, 1H), 6.78(d, 1H), 6.97(t, 1H), 7.14(m,4H), 7.36(d, 2H), 7.57(m, 1H), 7.91(d, 2H), 9.56(s, 1H); Mass Spectrum:M + H⁺ 469. Method 73 4

Mass Spectrum: M + H⁺ 461 CAS no. 13288-06-7 J. Prakt. Chem., 1881, 2425

Mass Spectrum: M + H⁺ 366 6

Mass Spectrum: M + H⁺ 386 7

Mass Spectrum: M + H⁺ 458 8

Mass Spectrum: M + H⁺ 485 9

Mass Spectrum: M + H⁺ 432 10

Mass Spectrum: M + H⁺ 394 CAS no. 53012-70-7 J. Het. Chem. 1984, 1157 11

Mass Spectrum: M + H⁺ 466 12

Mass Spectrum: M + H⁺ 378 13

Mass Spectrum: M + H⁺ 473 CAS no 57011-90-2 Justus Liebigs Ann. Chem.1899, 287 DE 85988 14

Mass Spectrum: M + H⁺ 368 15

Mass Spectrum: M + H⁺ 394

EXAMPLE 24

Using an analogous procedure to that described in Example 19,N-(2-aminophenyl)-4-piperazin-1-ylbenzamide (Example 16) was reacted togive the compounds described in Table 9. TABLE 9

Note R¹ Analytical Data SM 1

NMR Spectrum: (CDCl₃)2.62(t, 2H), 2.78(m, 6H), 3.45(m, 4H), 6.83(m, 2H),7.07(m, 3H), 7.26(s, 1H), 7.31(d, 1H), 7.74(s, 1H), 7.84(d, 2H), 7.96(d,2H), 8.41(t, 1H), 11.07(s, 1H); Mass Spectrum: M + H⁺462. 2

NMR Spectrum: (CDCl₃)2.74(m, 4H), 3.29(s, 2H), 3.37(m, 4H), 3.74(s, 3H),6.71(m, 2H), 6.90(d, 2H), 7.06(t, 1H), 7.28(d, 1H), 7.77(s, 1H), 7.80(d,2H); Mass Spectrum: M + H⁺ 369. 3

NMR Spectrum: (CDCl₃)2.61(m, 4H), 3.33(m, 4H), 3.57(s, 2H), 6.81(m, 4H),6.91(m, 2H), 7.06(m, 2H), 7.34(m, 3H), 7.72(s, 1H), 7.80(d, 2H); MassSpectrum: M + H⁺ 387. 4

NMR Spectrum: (CDCl₃)1.21(t, 6H), 2.77(4H), 3.43(m, 10H), 3.78(s, 2H),6.62(d, 2H), 6.83(m, 2H), 6.93(d, 2H), 7.07(t, 1H), 7.30(d, 1H), 7.69(s,1H), 7.81(d, 2H), 7.93(d, 2H); Mass Spectrum: M + H⁺486.Preparation of the Starting Materials

The starting materials for the above examples are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example the following reactions are illustrations but notlimitations of the preparation of some of the starting materials used inthe above reactions.

Method 1

N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-4-ylbenzamide

N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method 14; 136 mg,0.33 mmol), pyridine-4-boronic acid (48 mg, 0.39 mmol),tetrakis(triphenylphosphine)palladium (5 mg, 0.005 mmol), THF (2 ml) anda saturated aqueous solution of sodium hydrogen carbonate (2 ml) werestirred at 55° C. under an atmosphere of argon for 96 hours. The cooledmixture was partitioned between ethyl acetate and water. The organicswere washed with brine, dried over magnesium sulfate, filtered andevaporated, to give the title compound (103 mg, 80%), which was usedwithout further purification; Mass Spectrum: M+H⁺ 390.

Method 2

N-(2-t-Butoxycarbonylaminophenyl)-4-quinolin-8-ylbenzamide

N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method 14; 200 mg,0.5 mmol), 8-quinoline boronic acid (104 mg, 0.6 mmol),tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol),1,2-dimethoxyethane (3 ml) and a saturated aqueous solution of sodiumhydrogen carbonate (3 ml) were stirred at 80° C. under an atmosphere ofargon for 20 hours. The mixture was allowed to cool before beingpartitioned between ethyl acetate and water. The organics were washedwith brine, dried over magnesium sulfate, filtered and evaporated. Theresultant residue was purified by flash column chromatography, elutingwith methanol/dichloromethane (0-10%), to give the title compound (201mg, 84%); NMR Spectrum: (DMSO-d₆): 1.47 (s, 9H), 7.20 (m, 2H), 7.60 (m,4H), 7.73 (t, 1H), 7.84 (t, 3H), 8.06 (d, 2H), 8.47 (d, 1H), 8.68 (s,1H), 8.93 (m, 1H), 9.91 (s, 1H), Mass Spectrum: M+H⁺: 440.

Method 3

N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-3-ylbenzamide

The title compound was prepared using an analogous procedure of Method 2and used without further purification; Mass Spectrum: M+H⁺ 390.

Method 4

N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-2-ylbenzamide

N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13; 132 mg, 0.3 mmol), 2-bromopyridine (40 mg, 0.25 mmol),tetrakis(triphenylphosphine)palladium (4 mg, 0.004 mmol),1,2-dimethyoxyethane (1.5 ml) and a saturated aqueous solution of sodiumhydrogen carbonate (1.5 ml) were stirred at 80-85° C. under anatmosphere of argon for 24 hours. The mixture was allowed to cool beforebeing partitioned between ethyl acetate and water. The organics wereseparated, washed with brine, dried over magnesium sulfate, filtered andevaporated to yield the title compound (86 mg, 74%) which was used inthe next reaction without further purification; Mass Spectrum: M+H⁺ 390.

Method 5-12

Using an analogous procedure to that described in Method 4, theN-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamidestarting material was reacted with the appropriate bromo compound togive the compounds described in Table 10. Where required, the cruderesidues were purified by flash column chromatography, eluting withmethanol/dichloromethane (1:10). TABLE 10

Method R¹ Analytical Data SM 5 6-(methoxy)-1,2-pyrazin-3-yl NMRSpectrum: (DMSO-d₆)1.44(s, Meth 13 9H), 4.09(s, 3H), 7.14(m, 2H),7.34(d, 1H), 7.57(t, 2H), 8.09(d, 2H), 8.22(d, 2H), 8.26(d, 1H); MassSpectrum: M + H⁺ 421. 6 furan-3-yl Mass Spectrum: (M + H⁺—tBu)323. Meth13 7 2-methylpridin-4-yl NMR Spectrum: (DMSO-d₆)1.46(s, Meth 13 9H),2.57(s, 3H), 7.20(m, 2H), 7.59(m, 3H), 7.69(s, 1H), 7.98(d, 2H), 8.10(d,2H), 8.56(d, 1H), 8.67(s, 1H), 9.92(s, 1H); Mass Spectrum: M + H⁺ 404. 82-fluoropyridin-4-yl NMR Spectrum: (DMSO-d₆)1.46(s, Meth 13 9H), 7.20(m,2H), 7.57(m, 2H), 7.65(s, 1H), 7.81(m, 1H), 8.06(d, 2H), 8.12(d, 2H),8.37(d, 1H), 8.68(s, 1H), 9.94(s, 1H); Mass Spectrum: (M + H⁺—Boc)308. 9thiazol-2-yl Mass Spectrum: (M + H⁺—tBu)340. Meth 13 102-amino-pyrimidn-6-yl Mass Spectrum: (M + Na⁺)428. Meth 13 11pyrimidin-6-yl Mass Spectrum: (M + H⁺—tBu)335. Meth 13 122-chloro-pyrimidin-6-yl NMR Spectrum: (DMSO-d₆)1.46(s, Meth 13 9H),7.23(m, 2H), 7.57(t, 2H), 8.15(d, 2H), 8.29(d, 1H), 8.38(d, 2H),8.73(br, 1H), 8.91(d, 1H), 10.00(s, 1H); Mass Spectrum: (M + H⁺—tBu)369.Method 13

N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method 14; 3.0 g,7.7 mmol) was added to a solution of bis-pinacolato diboron (2.3 g, 9.2mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II)chloride (157 mg, 0.19 mmol) and potassium acetate (2.3 g, 23 mmol) inDMF (48 ml) at 80° C. under an atmosphere of argon for 20 hours. Themixture was allowed to cool and the solvent removed in vacuo. Theresidue was partitioned between ethyl acetate and water. The organicswere washed with brine, dried over magnesium sulphate and evaporated togive the title compound (3.9 g, quantitative), which was used withoutfurther purification; NMR Spectrum: DMSO-d₆) 1.14 (s, 6H), 1.31 (s, 9H),1.43 (s, 6H), 7.16 (m, 2H), 7.52 (m, 2H). 7.79 (d, 2H), 8.66 (s, 1H),9.86 (s, 1H); Mass Spectrum: (M+H⁺-Boc) 383.

Method 14

N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide

4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride(Method 18; 5.4 g, 19.4 mmol) was added to a solution of 4-bromobenzoicacid (3.5 g, 17.4 mmol) and 1-(N-t-butoxycarbonylamino)-2-aminobenzene(Method 17; 4.3 g, 20.9 mmol) in DMF (100 ml) and stirred at ambienttemperature for 20 hours. The reaction mixture was partitioned betweenwater and ethyl acetate. The organics were washed with a saturatedaqueous solution of sodium hydrogen carbonate, water, 1M aqueoushydrochloric acid, water and brine, before being dried over magnesiumsulfate. The organics were then evaporated to give the title compound(7.1 g, quantitative), which was used without further purification. NMRSpectrum: (DMSO-d₆): 1.45 (s, 9H), 7.18 (m, 2H), 7.54 (m, 2H), 7.76 (d,2H). 7.90 (d, 2H), 8.63 (s, 1H), 9.86 (s, 1H); Mass Spectrum: (M+H⁺-Boc)291.

Method 15

N-(2-t-Butoxycarbonylaminophenyl)-4-(1-t-butoxycarbonylpiperidin-4-yl)benzamide

1-(N-t-Butoxycarbonylamino)-2-aminobenzene (Method 17, 3.1 g, 14.7 mmol)was added to a stirred solution of4-(1-t-butoxycarbonylpiperidin-4-yl)benzoic acid (4.1 g, 13.4 mmol) inDMF (50 ml) and the mixture stirred at ambient temperature for 10minutes. 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholiniumchloride (Method 18, 4.45 g, 16.1 mmol) was added and the mixturestirred at ambient temperature for 24 hours. The solvent was evaporatedand the residue was dissolved in ethyl acetate (100 ml) and washed withwater. The organics were dried over magnesium sulfate, filtered andevaporated. The resultant gum was purified by flash chromatography using1% methanol/dichloromethane to give the title compound as a foam (5.44g, 82%); NMR Spectrum: (DMSO-d₆) 1.41 (s, 9H), 1.43 (s, 9H), 1.54 (m,2H), 1.77 (m, 2H), 2.79 (m, 3H), 4.08 (m, 2H), 7.15 (m, 2H), 7.40 (d,2H), 7.52 (m, 2H), 7.87 (d, 2H), 8.60 (br, 1H), 9.74 (br, 1H), MassSpectrum: (M+H⁺-Boc) 396.

Method 16

N-(2-t-Butoxycarbonylaminophenyl)-4-(1-methylpiperazin-4-yl)benzamide

4-(1-Methylpiperazin-4-yl)benzoic acid (250 mg, 1.13 mmol) and1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 331 mg, 1.59mmol) were dissolved in DMF (3 ml).4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride(Method 18, 313 mg, 1.13 mmol) was added and the resulting solution wasstirred for 20 hours at ambient temperature. The solution was pouredinto water and extracted several times with ethyl acetate. The combinedorganic extracts were dried over magnesium sulfate and evaporated. Theresidue was purified by flash chromatography (eluting with 99:1→9:1dichloromethane:methanol) to afford the title compound as a colourlessgum which crystallised on trituration (240 mg, 52%); Mass Spectrum: M+H⁺411.

Method 17

1-(N-t-Butoxycarbonylamino)-2-aminobenzene

The title compound was prepared according to the literature methoddescribed in Seto, C, T.; Mathias, J. P.; Whitesides, G. M.; J. Am.Chem. Soc., 1993, 115, 1321-1329.

Method 18

4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride

4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride wasprepared according to the literature procedure described in Kunishima,M., Kawachi, C., Morita, J., Terao, K., Iwasaki, F., Tani, S.,Tetrahedron, 1999, 55, 13159-13170.

Method 19

N-(2-Aminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamidetrihydrochloride

N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamide(Method 20, 64 mg, 0.120 mmol) was suspended in 1,4 dioxane (1.5 ml) anda 4M solution of hydrogen chloride in 1,4-dioxane (1 ml) added. Thereaction mixture was stirred at ambient temperature for 64 hours. Thereaction mixture was diluted with diethyl ether, and the resultantprecipitate was collected by filtration, washed with diethyl ether andair dried, to yield the title compound (as its hydrochloride salt) as anoff white solid (62 mg, 95%); Mass Spectrum: M+H⁺ 433.

Method 20

N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamide

N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzamide(Method 21, 62.5 mg, 0.133 mmol) was dissolved in a mixture of THF (2ml) and N,N-dimethylacetamide (2 ml) and N-(3-aminopropyl)morpholine (60μl, 0.411 mmol) added. The reaction mixture was heated to 50° C. andstirred for 2 hours. The reaction mixture was then cooled and solventsremoved under reduced pressure. The resultant oil was purified byelution through silica with a 5% methanol in dichloromethane, to yieldthe title compound as a colourless solid (65 mg, 92%); NMR Spectrum:DMSO-d₆) 1.45 (s, 9H), 1.74 (m, 2H), 2.37 (m, 6H), 3.40 (br, 2H), 3.59(m, 4H), 7.20 (m, 2H), 7.23 (d, 1H), 7.34 (t, 1H), 7.57 (d, 1H), 8.08(d, 2H), 8.26 (d, 2H), 8.40 (m, 1H), 8.72 (s, 1H), 9.94 (s, 1H); MassSpectrum: M+H⁺ 534.

Method 21

N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzamide

N-(2-t-Butoxyaminophenyl)-4-(2-thiomethyl-pyrimidin-6-yl)benzamide(Method 22, 140 mg, 0.32 mmol) was dissolved in methanol (8 ml) and asmall amount of ethyl acetate, followed by a solution of Oxone® (630 mg,1.02 mmol) in water (4 ml). The resultant suspension was stirred atambient temperature for 1 hour before being partitioned between ethylacetate and a mixture of water and saturated sodium bicarbonate. Theorganic phase was separated and the aqueous phase extracted with furtheraliquots of ethyl acetate. The combined organic extracts were washedwith brine and dried over magnesium sulfate. Evaporation to drynessafforded the title compound as an off white powder (126 mg, 84%); NMRSpectrum: (DMSO-d₆) 1.45 (s, 9H), 3.54 (s, 3H), 7.20 (m, 2H), 7.57 (t,2H), 8.18 (d, 2H), 8.48 (d, 2H), 8.54 (s, 1H), 8.73 (s, 1H), 9.20 (d,1H), 10.02 (s, 1H); Mass Spectrum: (M+H⁺-Boc) 369.

Method 22

N-(2-t-Butoxyaminophenyl)-4-(2-thiomethyl-pyrimidin-6-yl)benzamide

4-Iodo-2-methylthiopyrimidine (Method 23, 360 mg, 1.43 mmol) was reactedwithN-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 631 mg, 1.44 mmol) in an analogous manner to that describedin Method 4 to yield the crude title compound. This was purified byelution through silica with a solution of ethyl acetate in isohexane(25% to 50% (v/v)) to afford the pure title compound as a pale yellowfoam (306 mg, 49%); NMR Spectrum: (DMSO-d₆) 1.45 (s, 9H), 2.63 (s, 3H),7.20 (m, 2H), 7.57 (t, 2H), 7.91 (d, 1H), 8.13 (d, 2H), 8.37 (d, 2H),8.72 (s, 1H), 8.77 (d, 1H), 9.97 (s, 1H); Mass Spectrum: (M+H⁺-tBu) 381.

Method 23

4-Iodo-2-methylthiopyrimidine

4-Chloro-2-methylthiopyrimidine (5 g, 31.15 mmol) was added dropwise toa cooled 57% aqueous hydriodic acid solution (0° C.). Stirring wascontinued at 0° C. for 30 minutes, before warming to ambient temperatureand stirring for 24 hours. Aqueous sodium bicarbonate was then carefullyadded and the resultant suspension basified to pH 9 by addition ofsodium carbonate. The mixture was extracted with ethyl acetate and theextracts dried over magnesium sulfate and concentrated by reducedpressure. The resultant solid was dissolved in boiling isohexane andcooled by refrigeration overnight. The resultant solid was filtered anddried to afford the title compound as colourless needles (5.4 g, 69%);NMR Spectrum: (CDCl₃) 2.55 (s, 3H), 7.40 (d, 1H), 7.98 (d, 1H); MassSpectrum: M+H⁺ 253.

Method 24

N-(2-Aminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benzamidetrihydrochloride

N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benzamide(Method 25, 59 mg, 0.113 mmol) was reacted in an analogous manner tothat described for Method 19 to yield the title compound (as itshydrochloride salt) as a beige solid (56 mg, 94%); Mass Spectrum:M+H⁺419.

Method 25

N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benzamide

N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzamide(Method 21, 62.5 mg, 0.133 mmol) was reacted withN-(2-aminoethyl)morpholine (60 μl, 0.457 mmol) in an analogous manner tothat described in method 20 to yield the title compound as a pale yellowsolid (66 mg, 96%); NMR Spectrum: (DMSO-d₆) 1.46 (s, 9H), 2.45 (brm,4H), 3.30 (m, 2H), 3.50 (brm, 2H), 3.58 (m, 4H), 7.14 (t, 1H), 7.17 (m1H), 7.22 (m, 1H), 7.25 (d, 1H), 7.57 (d, 2H), 8.09 (d, 2H), 8.27 (d,2H), 8.42 (d, 1H), 8.73 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M+H⁺ 519.

Method 29

N-(2-t-butoxycarbonylaminophenyl)-4-{2-[(3-piperidin-1-ylpropyl)amino]pyrimidin-4-yl}benzamide

To a 24 mm×150 mm pyrex tube, charged with 3-aminopropylpiperidine (73mg, 0.51 mmol), was added a solution ofN-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide(Method 52, 85 mg, 0.20 mmol) in N,N-dimethylacetamide (4.6 ml). Thereaction mixture was then heated to 50° C. and stirred for 16 hours,before being evaporated to dryness. The resultant residue was purifiedby flash chromatography, on silica (10 g), eluting withmethanol/dichloromethane (5-15%), to give the title compound (48 mg,45%); Mass Spectrum: M+H⁺ 531.

Method 30-36

Using an analogous procedure to that described in Method 29, theN-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamidestarting material (Method 52) was reacted with the appropriate amine togive the compounds described in Table 11. Where required, the cruderesidues were purified by flash column chromatography, on silica (10 g),eluting with methanol/dichloromethane (5-15%). TABLE 11

Method R¹ Analytical Data SM 30

Mass Spectrum: M+H⁺514. 31

Mass Spectrum: M+H⁺546. 32

Mass Spectrum: M+H⁺533. 33

Mass Spectrum: M+H⁺505. 34

Mass Spectrum: M+H⁺497. 35

Mass Spectrum: M+H⁺517. 36

Mass Spectrum: M+H⁺478. Meth 52Method 37

N-(2-t-butoxycarbonylaminophenyl)-4-[2-(3-morpholin-4-ylpropoxy)pyridin-4-yl]benzamide

To a suspension of sodium hydride in tetrahydrofuran (1 ml) was added,dropwise, via syringe, a solution of 3-N-morpholinopropanol (147 mg,1.01 mmol). The reaction mixture was stirred, under an argon atmosphere,for 30 minutes, then added, via cannula, to a solution ofN-(2-t-butoxycarbonylaminophenyl)-2-fluoropyridin-4-ylbenzamide (Method8, 119 mg, 0.29 mmol) in tetrahydrofuran (2 ml). The mixture was thenstirred, under an argon atmosphere, for 2 hours at ambient temperature,before being heated to 50° C. and stirred for a further 5.5 hours. Thereaction mixture was allowed to cool before being partitioned betweenethyl acetate and water. The organics were separated and aqueousextracted further with ethyl acetate. The combined organic layers werethen combined, washed with brine, dried over magnesium sulfate, filteredand evaporated. The resultant residue was purified by flashchromatography, on silica (20 g), eluting with methanol/dichloromethane(0-10%), to give the title compound (70 mg, 45%); NMR Spectrum:(DMSO-d₆) 1.46 (s, 9H), 1.92 (m, 2H), 2.38 (m, 4H), 2.45 (m, 2H), 3.59(t, 4H), 4.36 (t, 2H), 7.20 (m, 3H), 7.39 (dd, 1H, 7.57 (d, 2H), 7.97(d, 2H), 8.08 (d, 2H), 8.26 (d, 1H), 8.67 (s, 1H), 9.91 (s, 1H); MassSpectrum: M+H⁺ 533.

Method 38

N-(2-t-butoxycarbonylaminophenyl)-4-(6-methylpyridin-3-yl)benzamide

Using an analogous procedure to that described in Method 4,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 1.20 g, 2.74 mmol) was reacted with 2-methyl-5-bromopyridine(505 mg, 2.94 mmol). The crude residue was purified by flashchromatography on silica (90 g), eluting with ethyl acetate/isohexane(40-100%) to give the title compound (504 mg, 46%); NMR Spectrum:(DMSO-d₆) 1.46 (s, 9H), 2.51 (s, 3H), 7.19 (m, 2H), 7.40 (d, 1H), 7.58(m, 2H), 7.91 (d, 2H), 8.08, (d, 3H), 8.66 (s, 1H), 8.86 (d, 1H), 9.89(s, 1H); Mass Spectrum: M+H⁺ 404.

Method 39

N-(2-t-butoxycarbonylaminophenyl)-4-{2-[(3-piperidin-1-ylpropyl)amino]thieno[3,2-d]pyrimidin-4-yl}benzamide

A solution of 3-aminopropylpiperidine (60 μl, 0.38 mmol) andN-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)thieno[3,2-d]pyrimidin-4-yl]benzamide(Method 54, 81 mg, 0.15 mmol) in N,N-dimethylacetamide was heated firstto 50° C. for 23 hours and then further heated to 75° C. for a period of16 hours. The reaction mixture was evaporated to dryness and the cruderesidue purified by flash chromatography, on silica (10 g), eluting withmethanol/dichloromethane (0-15%) to give the title compound (23 mg,26%); Mass Spectrum: M+H⁺ 587.

Method 40

N-(2-t-butoxycarbonylaminophenyl)-4-thieno[3,2-d]pyrimidin-4-ylbenzamide

Using an analogous procedure to that described in Method 4,4-chlorothieno[3,2-d]pyrimidine (538 mg, 3.15 mmol) was reacted withN-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 1.53 g, 3.50 mmol). The crude residue was purified by flashchromatography, on silica, eluting with ethyl acetate/hexane (25-75%) togive the title compound (1.08 g, 69%); NMR Spectrum: DMSO-d₆) 1.47 (s,9H), 7.21 (m, 2H), 7.57 (t, 2H), 7.79 (d, 1H), 8.23 (d, 2H), 8.34 (d,2H), 8.64 (d, 1H, 8.75 (s, 1H), 9.35 (s, 1H), 10.03 (s, 1H); MassSpectrum: M+H⁺ 447.

Method 41

N-(2-aminophenyl)-4-{2-[(3-piperidin-1-ylpropyl)amino]pyrimidin-5-yl}benzamide

To a solution ofN-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide(Method 53, 80 mg, 0.19 mmol) in N,N-dimethylacetamide (3.5 ml) wasadded 3-aminopropylpiperidine (108 mg 0.76 mmol). The reaction mixturewas stirred at 50° C. for 20 hours, before being allowed to cool. Thereaction mixture was partitioned between water and ethyl acetate, beforebeing filtered under gravity, through a Varian Chem Elut (CE1010)diatomaceous earth column. The resulting solution was then concentratedunder reduced pressure and purified by flash column chromatography,eluting with methanol/dichloromethane (0-20%), to give the titlecompound, which was used without further purification; Mass Spectrum:M+H⁺ 531.

Method 42-43

Using an analogous procedure to that described in method 41, theN-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide(Method 53) was reacted with the appropriate amine to give the compoundsdescribed in Table 12. Where required, the crude residues were purifiedby flash column chromatography, on silica (10 g), eluting withmethanol/dichloromethane (0-20%). TABLE 12

Method R¹ Analytical Data SM 42

Mass Spectrum: M+H⁺546 43

Mass Spectrum: M+H⁺533.Method 44

N-(2-t-butoxycarbonylaminophenyl)-3-fluoro-4-pyridin-3-ylbenzamide

t-Butyl 2-[(4-bromo-3-fluorobenzoyl)amino]phenylcarbamate (Method 63,205 mg, 0.5 mmol), 3-pyridine boronic acid (74 mg, 0.6 mmol),tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol),1,2-dimethoxyethane (3 ml) and a saturated aqueous solution of sodiumhydrogen carbonate (3 ml) were stirred at 80° C. under an atmosphere ofargon for 48 hours. The cooled mixture was partitioned between ethylacetate and water. The aqueous layer was removed using Varian Chem Elutcolumn (CE1010) and the resulting solution was then concentrated underreduced pressure and purified by flash column chromatography, elutingwith ethyl acetate/isohexane (25-75%), to give the title compound (186mg, 91%). Mass Spectrum: M+H⁺ 408.

Method 45

N-(2-t-butoxycarbonylaminophenyl)-4-[2-(2-pyrrolidin-1-ylethoxy)pyrimidin-5-yl]benzamide

Using an analogous procedure to that described in Method 44,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 219 mg, 0.5 mmol) was reacted with5-bromo-2-(2-pyrrolidin-1-ylethoxy)pyrimidine (Method 64, 136 mg, 0.5mmol) to give the title compound (71 mg; 28%). Mass Spectrum: M+H⁺ 504.

Method 46-50

Using an analogous procedure to that described in Example 1, theappropriate N-(2-t-butoxycarbonylaminophenyl)benzamide starting materialwas reacted to give the compounds described in Table 13, as theirhydrochloride salt. TABLE 13

Method R¹ Analytical Data SM 46

Mass Spectrum: M+H⁺432. Meth 56 47

Used without further purification. Meth 57 48

Mass Spectrum: M+H⁺375. Meth 58 49

Mass Spectrum: M+H⁺378 Meth 59 50

Mass Spectrum: M+H⁺389 Meth 60Method 51

N-(2-t-butoxycarbonylaminophenyl)-4-[5-(piperidin-1-ylmethyl)-1,3-thiazol-2-yl]benzamide

Using an analogous procedure to that described in Method 44,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 219 mg, 0.5 mmol) was reacted with1-[(2-chloro-1,3-thiazol-5-yl)methyl]piperidine (108 mg, 0.5 mmol) togive the title compound (271 mg, >100%) which was carried through thenext step; Mass Spectrum: M+H⁺ 493.

Method 52

N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide

Using an analogous procedure to that described in Method 4,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 3.9 g, 8.9 mmol) was reacted with 2,4-dichloropyrimidine(3.06 g, 20.5 mmol). The crude residue was purified by flashchromatography on silica, eluting with ethyl acetate/isohexane (1:1) togive the title compound (1.2 g, 32%); NMR Spectrum: (DMSO-d₆) 1.45 (s,9H), 7.23 (m, 2H), 7.57 (t, 2H), 8.15 (d, 2H), 8.29 (d, 1H), 8.38 (d,2H), 8.73 (s, 1H), 8.91 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M−H⁻ 423.

Method 53

N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide

N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 4.0 g, 9.12 mmol), 5-bromo-2-chloropyrimidine (1.76 g, 9.12mmol), tetrakis(triphenylphosphine)palladium (527 mg, 0.46 mmol),1,2-dimethoxyethane (40 ml) and a saturated aqueous solution of sodiumhydrogen carbonate (40 ml) were stirred at 80° C. under an atmosphere ofargon for 18 hours. The cooled mixture was concentrated under reducedpressure. The residue was then stirred with ethyl acetate for 1 hour andthe resultant solid collected by suction filtration and dried to givethe title compound (2.38 g; 61%); NMR Spectrum: (DMSO-d₆) 1.47 (s, 9H),7.20 (m, 2H), 7.58 (d, 2H), 8.02 (d, 2H), 8.11 (d, 2H), 8.66 (s, 1H),9.23 (s, 2H), 10.93 (s, 1H); Mass Spectrum: M+H⁺-^(t)Bu 369.

Method 54

N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)thieno[3,2-d]pyridin-4-yl]benzamide

To a cooled (0° C.) solution ofN-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylthio)thieno[3,2-d]pyrimidin-4-yl]benzamide(Method 55, 960 mg, 1.95 mg) in DMF (40 ml), was addedmeta-chloroperbenzoic acid (57%, 630 mg, 2.08 mmol) and the reactionmixture stirred, allowing warning to ambient temperature. After 3 hoursa further portion of meta-chloroperbenzoic acid (70%, 589 mg, 2.40 mmol)was added and stirring continued for 2 hours. The reaction mixture wasthen carefully poured into aqueous sodium metabisulfite solution (0.25M,100 ml), before addition of ethyl acetate (100 ml). The insolublematerial was removed by filtration and dried in vacuo to yield the titlecompound (586 mg, 57%); NMR Spectrum: (DMSO-d₆) 1.46 (s, 9H), 3.57 (s,3H), 7.18 (t, 1H), 7.24 (t, 1H), 7.59 (m, 2H), 8.00 (d, 1H), 8.27 (d,2H), 8.41 (d, 2H), 8.75 (s, 1H), 8.90 (d, 1H), 10.07 (s, 1H; MassSpectrum: M+Na⁺ 547.

Method 55-59

Using an analogous procedure to that described in Method 4,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13) was reacted with the appropriate halide to give thecompounds described in Table 14. Where appropriate compounds werefiltered from reaction mixtures following partitioning or if required,the crude residues were purified by flash column chromatography, onsilica eluting with methanol/dichloromethane (0-20%). TABLE 14

Method R¹ Analytical Data SM 55

NMR Spectrum: (DMSO-d₆) 1.46 (s, 9H), 2.67 (s, 3H), 7.17 (t, 1H), 7.23(t, 1H), 7.59 (t, 2H), 7.65 (d, 1H), 8.22 (d, 2H), 8.30 (d, 2H), 8.59(d, 1H), 8.75 (brs, 1H), 10.03 (s, 1H); Mass Spectrum: M+H⁺493.[CAS176530-47-5] 56

NMR Spectrum: (DMSO-d₆) 1.46 (s, 9H), 1.72 (m, 2H), 2.37 (m, 6H), 3.33(m, 2H), 3.58 (t, 4H), 6.62 (t, 1H), 6.77 (s, 1H), 6.83 (d, 1H), 7.19(m, 2H), 7.56 (d, 2H), 7.81 (d, 2H), 8.07 (m, 3H), 8.66 (s, 1H), 9.89(s, 1H); Mass Spectrum: M+H⁺532. Meth 61 57

NMR Spectrum: (DMSO-d₆) 1.47 (s, 9H), 3.92 (s, 3H), 7.18 (m, 2H), 7.59(m, 2H), 8.18 (d, 2H), 8.70 (s, 1H), 9.00 (d, 2H), 9.06 (s, 1H), 9.97(brs, 1H); Mass Spectrum: M+H⁺445. [CAS2346-74-9] 58

Mass Spectrum: M+H⁺-Boc 376. [CAS61655-58-1] 59

Mass Spectrum: M+H⁺479. [CAS122-34-9]Method 60

N-(2-t-Butoxycarbonylaminophenyl)-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzamide

Using an analogous procedure to that described in Method 41, theN-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide(Method 52, 59 mg, 0.14 mmol) was reacted with 1-methylpiperazine (77mg, 0.69 mmol) and residue purified by flash chromatography eluting withmethanol/dichloromethane (0-20%) to give the title compound (48 mg,71%); Mass Spectrum: M+H⁺ 489.

Method 61

4-Iodo-N-(3-morpholin-4-ylpropyl)pyridin-2-amine

A solution of 4-iodo-2-fluoropyridine (2.32 g, 10.00 mmol) andN-(3-aminopropyl)morpholine (4.2 ml, 26.00 mmol) inN,N-dimethylacetamide (30 ml) was heated to 100° C. for 20 hours beforebeing concentrated in vacuo, to afford the crude title compound whichwas used without any further purification; Mass Spectrum: M+H⁺ 348.

Method 62

N-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide

Using an analogous procedure to that described in Example 1,N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide(Method 21, 1.097 g, 2.34 mmol) was reacted to give the title compoundas its hydrochloride salt (1.01 g, 98%); NMR Spectrum: (DMSO-d₆) 3.53(s, 3H), 7.31 (m, 3H), 7.52 (d, 1H), 8.30 (d, 2H), 8.48 (d, 2H), 8.53(d, 1H), 9.20 (d, 1H), 10.56 (s, 1H); Mass Spectrum: M+H⁺ 369.

Method 63

t-Butyl 2-[(4-bromo-3-fluorobenzoyl)amino]phenylcarbamate

1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 1.25 g, 6 mmol)was reacted with 4-bromo-3-fluorobenzoic acid (1.1 g, 5.0 mmol) in ananalogous manner to that described in Method 16 to give the titlecompound, which was used without further purification; Mass Spectrum:(M+H⁺-Boc) 311.

Method 64

5-bromo-2-(2-pyrrolidin-1-ylethoxy)pyrimidine

To a solution of N-2-hydroxyethylpyrrolidine (0.9 ml, 7.71 mmol) and5-bromo-2-chloropyrimidine (1.2 g, 6.20 mmol), in DMF (7 ml), was addedsodium hydride (60% in mineral oil, 0.35 g, 8.75 mmol). The mixture wasstirred, under argon, at ambient temperature for 1 hour, before beingheated to 90° C. and stirred for a further hour. The reaction mixturewas then partitioned between ethyl acetate and water. The organics wereseparated, dried over magnesium sulfate and evaporated to dryness. Theresultant oil was purified by flash chromatography on silica, elutingwith an increasing gradient of methanol in dichloromethane (whichcontained 1% aqueous ammonia solution, 0.88 M) to give the titlecompound (640 mg, 38%); NMR Spectrum: (CDCl₃) 1.76 (m, 4H), 2.39 (m,4H), 3.90 (t, 2H), 4.48 (t, 2H), 8.50 (s, 2H); Mass Spectrum: M+H⁺ 272.

Method 65-66

Using an analogous procedure to that described in Method 39,N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)thieno[3,2-d]pyrimidin-4-yl]benzamide(Method 54) was reacted with the appropriate amine to give the compoundsdescribed in Table 15. The resultant residues, where required, werepurified by flash chromatography on silica, eluting withmethanol/dichloromethane (0-15%). TABLE 15

Method R¹ Analytical Data SM 65

Used without further purification. 66

Mass Spectrum: M+H⁺573.Method 67

[2-(4-{[(2-t-Butoxycarbonylaminophenyl)amino]carbonyl}phenyl)-1,3-thiazol-5-yl]methylcyclohexylcarbamate

Using an analogous procedure to that described in Method 4,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 219 mg, 0.5 mmol) was reacted with(2-chloro-1,3-thiazol-5-yl)methyl cyclohexylcarbamate (138 mg, 0.5mmol). The crude residue was stirred in ethyl acetate for 16 hoursbefore being filtered, mixed with water and the aqueous removed using aVarian Chem Elut Column (CE1010). The resulting solution wasconcentrated and purified by flash chromatography on silica, elutingwith methanol/dichloromethane (0-30%) to give the title compound; MassSpectrum: M+H⁺ 551.

Method 68

N-(2-t-butoxycarbonylaminophenyl)-4-{5-[2-(methylthio)pyrimidin-4-yl]thien-2-yl}benzamide

Using an analogous procedure to that described in Method 4,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 219 mg, 0.5 mmol) was reacted with4-(5-bromothien-2-yl)-2-(methylthio)pyrimidine (145 mg, 0.5 mmol). Thecrude residue stirred in ethyl acetate/water for 1 hour before beingfiltered, and the aqueous removed using a Varian Chem Elut Column(CE1010). The resulting solution was concentrated and recrystallisedfrom methanol to give the title compound; Mass Spectrum: M+H⁺-Boc 463.

Method 69

[2-(4-{[(2-t-butoxycarbonylaminophenyl)amino]carbonyl}phenyl)-1,3-thiazol-5-yl]methylphenylcarbamate

Using an analogous procedure to that described in Method 4,N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13, 219 mg, 0.5 mmol) was reacted with(2-chloro-1,3-thiazol-5-yl)methyl N-phenylcarbamate (136 mg, 0.5 mmol).The crude residue stirred in ethyl acetate/water for 16 hours beforebeing filtered, and the aqueous removed using a Varian Chem Elut Column(CE1010). The resulting solution was concentrated and purified by flashchromatography on silica, eluting with methanol/dichloromethane (0-30%)to give the title compound; Mass Spectrum: M+H⁺-Boc 489.

Method 70

[2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-1,3-thiazol-5-yl]methylphenylcarbamate

Using an analogous procedure to that described in Example 12, theappropriate N-(2-t-butoxycarbonylaminophenyl)benzamide starting materialwas reacted to give the compound described in Table 16, as itshydrochloride salt. TABLE 16 Structure Analytical Data SM

Mass Spectrum: M+H⁺445. Meth 69₅Method 71

t-Butyl4-{4-[({2-[(t-butoxycarbonyl)amino]phenyl}amino)carbonyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

A saturated solution of sodium hydrogen carbonate (3 ml) was added to astirred solution of t-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate(Method 72, 200 mg, 0.60 mmol) in 1,2-dimethoxyethane (3 ml).N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13) (318 mg, 0.72 mmol) was added followed bytetrakis(triphenylphosphine)palladium (100 mg, 0.09 mmol) and themixture stirred at 80° C. for 18 hours. The cooled mixture waspartitioned between ethyl, acetate and water. The organic phase wasseparated, then washed with water and dried over magnesium sulfate,filtered and evaporated. The resultant residue was purified by flashcolumn chromatography (eluting with 0-15% methanol in dichloromethane)to give the title compound (220 mg, 74%); NMR Spectrum: (DMSO-d₆) 1.42(s, 9H), 1.43 (s, 9H), 2.48 (m, 2H), 3.55 (m, 2H), 4.02 (m, 2H), 6.31(s, 1H), 7.17 (m, 2H), 7.52 (m, 2H), 7.58 (d, 2H), 7.92 (d, 2H), 8.62(s, 1H), 9.79 (s, 1H); Mass Spectrum: M+H⁺ 494.

Method 72

t-Butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6dihydropyridine-1(2H)-carboxylate

A 1.6 M solution of n-butyllithium in hexanes (6.9 ml, 11 mmol) wasadded to a stirred solution of diisopropylamine (1.5 ml, 11 mmol) in THFat −78° C. and the mixture stirred for 30 minutes. A solution of t-butyl4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) in THF was added andafter 20 minutes a solution of N-phenyl-bis(trifluoromethanesulfonimide)(3.9 g, 11 mmol) in THF was added. The mixture was stirred at ambienttemperature overnight and the solvent evaporated. The resultant residuewas partioned between diethyl ether and a 2M solution of aqueous sodiumhydroxide, the organic layer separated, washed once with brine and driedover magnesium sulfate, filtered and evaporated to give the titlecompound (3.01 g, 83%); NMR Spectrum: (DMSO-d₆) 1.48 (s, 9H), 2.44 (m,2H), 3.63 (t, 2H), 4.04 (d, 2H), 5.76 (s, 1H).

Method 73

1-Bromoacetyl-1,2,3,4-tetrahydroquinoline

1,2,3,4-tetrahydroquinoline (10 g, 75 mmol) was dissolved in benzene (40ml) and cooled to 10° C. A solution of bromoacetyl bromide (16 g, 80mmol) in benzene (40 ml) was added dropwise over 1 hour. The mixture wasstirred for a further 15 minutes. A 2M aqueous solution of sodiumhydroxide (500 ml) was added. The organic layer was separated, washedwith water (100 ml), dried over magnesium sulfate and evaporated toafford the crude product as an oil. This was purified by distillationunder reduced pressure followed by recrystallisation from 60-80petroleum ether to afford the product as a colourless solid (12.5 g,66%). Anal. Calc. for C₁₁H₁₂ONBr gives C 52.0%, H 4.8%, N 5.5%, Br31.4%; found C 51.9%, 4.8%, N 5.6%, Br 30.9%.

Method 74-75

Using an analogous procedure to that described in Method 4,N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Method 13) was reacted with the requisite chloroheterocycle to give thecompounds described in Table 17 TABLE 17

Method R¹ Analytical Data SM 74

Mass Spectrum: M+H⁺446. Meth 76 75

NMR Spectrum: (DMSO-d₆) 1.47 (s, 9H), 7.21 (m, 2H), 7.58 (m, 2H), 7.78(d, 1H), 8.12 (d, 1H), 8.19 (m, 4H), 8.71 (s, 1H), 9.23 (s, 1H), 10.01(s, 1H); Mass Spectrum: M+H⁺347.Method 76

7-chlorothieno[3,2-b]pyridine

Thieno[3,2,b]pyridin-7-ol (200 mg; 1.32 mmol) was added to thionylchloride (1.57 g; 13.2 mmol), followed by a drop of DMF. The solutionwas stirred at 80° C. for 4 hours. The cooled solution was diluted withethyl acetate and neutralised to pH 7 with a saturated solution ofsodium hydrogen carbonate (25 ml). The organic layer was washed withbrine, dried and concentrated to yield the title compound (112 mg; 50%);Mass Spectrum: M+H⁺ 170.

1. A compound of the formula (I):

wherein: Ring A is a heterocyclyl, wherein if said heterocyclyl containsan —NH— moiety that nitrogen may be optionally substituted by a groupselected from K; R¹ is a substituent on carbon and is selected fromhalo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, aryl, aryloxy, arylC₁₋₆alkyl, heterocyclicgroup, (heterocyclic group)C₁₋₆alkyl, or a group (B-E-); wherein R¹,including group (B-E-), may be optionally substituted on carbon by oneor more W; and wherein if said heterocyclic group contains an —NH—moiety that nitrogen may be optionally substituted by J; W is halo,nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, or a group (B′-E′-); wherein W, includinggroup (B′-E′-), may be optionally substituted on carbon by one or moreY; Y and Z are independently selected from halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl orN,N—(C₁₋₆alkyl)₂sulphamoyl; G, J and K are independently selected fromC₁₋₈alkyl, C₂₋₈-alkenyl, C₁₋₈alkanoyl, C₁₋₈alkylsulphonyl,C₁₋₈alkoxycarbonyl, carbamoyl, N—(C₁₋₈alkyl)carbamoyl,N,N—(C₁₋₈alkyl)carbamoyl, benzyloxycarbonyl, benzoyl, phenylsulphonyl,aryl, arylC₁₋₆alkyl or (heterocyclic group)C₁₋₆alkyl; wherein G, J and Kmay be optionally substituted on carbon by one or more Q; and wherein ifsaid heterocyclic group contains an —NH— moiety that nitrogen may beoptionally substituted by hydrogen or C₁₋₆alkyl; Q is halo, nitro,cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, N—(C₁₋₆alkyl)sulphamoyl,N,N—(C₁₋₆alkyl)₂sulphamoyl, aryl, aryloxy, aryl C₁₋₆alkyl,arylC₁₋₆alkoxy, heterocyclic group, (heterocyclic group)C₁₋₆alkyl,(heterocyclic group)C₁₋₆alkoxy, or a group (B″-E″-); wherein Q,including group (B″-E″-), may be optionally substituted on carbon by oneor more Z; B, B′ and B″ are independently selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈-cycloalkyl, C₃₋₈cycloalkylC₁₋₆alkyl,aryl, arylC₁₋₆alkyl, heterocyclic group, (heterocyclic group)C₁₋₆alkyl,phenyl or phenylC₁₋₆alkyl; wherein B, B′ and B″ may be optionallysubstituted on carbon by one or more D; and wherein if said heterocyclicgroup contains an —NH— moiety that nitrogen may be optionallysubstituted by a group selected from G; E, E′ and E″ are independentlyselected from —N(R^(a))—, —O—, —C(O)O—, —OC(O)—, —C(O)—, —N(R^(a))C(O)—,—N(R^(a))C(O)N(R^(b))—, —N(R^(a))C(O)O—, —OC(O)N(R^(a))—,—C(O)N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))—, —N(R^(a))SO₂—; wherein R^(a)and R^(b) are independently selected from hydrogen or C₁₋₆alkyloptionally substituted by one or more F and r is 0-2; D and F areindependently selected from halo, nitro, cyano, hydroxy,trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl orN,N—(C₁₋₆alkyl)₂sulphamoyl; m is 0, 1, 2, 3 or 4; wherein the values ofR¹ may be the same or different; R² is halo; n is 0, 1 or 2; wherein thevalues of R² may be the same or different; R³ is amino or hydroxy; R⁴ ishalo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₃alkyl, C₂₋₃alkenyl,C₂₋₃alkynyl, C₁₋₃alkoxy, C₁₋₃alkanoyl, C₁₋₃alkanoyloxy,N—(C₁₋₃alkyl)amino, N,N—(C₁₋₃alkyl)₂amino, C₁₋₃alkanoylamino,N—(C₁₋₃alkyl)carbamoyl, N,N—(C₁₋₃alkyl)₂carbamoyl, C₁₋₃alkylS(O)_(a)wherein a is 0 to 2, C₁₋₃alkoxycarbonyl, N—(C₁₋₃alkyl)sulphamoyl,N,N—(C₁₋₃alkyl)₂sulphamoyl; p is 0, 1 or 2; wherein the values of R⁴ maybe the same or different; or a pharmaceutically acceptable salt or invivo hydrolysable ester or amide thereof; with the proviso that saidcompound is notN-(2-amino-6-hydroxyphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;N-(2-amino-6-methylphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;N-(2-aminophenyl)-4-(1-t-butoxycarbonylhomopiperazin-4-yl)benzamide; orN-(2-aminophenyl)-4-(1-methylhomopiperazin-4-yl)benzamide.
 2. A compoundof the formula (I) according to claim 1 wherein: Ring A is a pyridyl,quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl,pyradazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl,thienopyridinyl, purinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl;wherein if Ring A contains an —NH— moiety that nitrogen may beoptionally substituted by a group selected from K.
 3. A compound of theformula (I) according to claim 1 wherein: R¹ is a substituent on carbonand is selected from halo, amino, C₁₋₆alkyl, C₁₋₆alkoxy,N—(C₁₋₆alkyl)amino, aryl, aryloxy, arylC₁₋₆alkyl, heterocyclic group,(heterocyclic group)C₁₋₆alkyl, or a group (B-E-); wherein R¹, includinggroup (B-E-), may be optionally substituted on carbon by one or more W;and wherein if said heterocyclic group contains an —NH— moiety thatnitrogen may be optionally substituted by J; W is hydroxy, mercapto,C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino or a group (B′-E′-);wherein W, including group (B′-E′-), may be optionally substituted oncarbon by one or more Y; Y and Z are independently selected from halo,nitro, cyano, hydroxy, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino orC₁₋₆alkanoylamino; G, J and K are independently selected from C₁₋₈alkyl,C₂₋₈alkenyl, C₁₋₈alkanoyl, aryl, arylC₁₋₆alkyl or (heterocyclicgroup)C₁₋₆alkyl; wherein G, J and K may be optionally substituted oncarbon by one or more Q; and wherein if said heterocyclic group containsan —NH— moiety that nitrogen may be optionally substituted by hydrogenor C₁₋₆alkyl; Q is cyano, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, aryl, aryloxy or a group(B″-E″-); wherein Q, including group (B″-E″-), may be optionallysubstituted on carbon by one or more Z; B, B′ and B″ are independentlyselected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkylC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic group,(heterocyclic group)C₁₋₆alkyl, phenyl or phenylC₁₋₆alkyl; wherein B, B′and B″ may be optionally substituted on carbon by one or more D; andwherein if said heterocyclic group contains an —NH— moiety that nitrogenmay be optionally substituted by a group selected from G; E, E′ and E″are independently selected from —N(R^(a))—, —O—, —C(O)O—, —OC(O)—,—C(O)—, —N(R^(a))C(O)—, —N(R^(a))C(O)N(R^(b))—, —N(R^(a))C(O)O—,—OC(O)N(R^(a))—, —C(O)N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))—,—N(R^(a))SO₂—; wherein R^(a) and R^(b) are independently selected fromhydrogen or C₁₋₆alkyl optionally substituted by one or more F and r is0-2; D and F are independently selected from halo, C₁₋₆alkoxy orN,N—(C₁₋₆alkyl)₂amino.
 4. A compound of the formula (I) according toclaim 1 wherein m is
 1. 5. A compound of the formula (I) according toclaim 1 wherein R² is fluoro and n is 0 or
 1. 6. A compound of theformula (I) according to claim 1 wherein R³ is amino.
 7. A compound ofthe formula (I) according to claim 1 wherein p is
 0. 8. A compound offormula (I) according to claim 1 wherein: Ring A is a pyridyl, quinolyl,indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl,pyradazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl,thienopyridinyl, purinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl;wherein if Ring A contains an —NH— moiety that nitrogen may beoptionally substituted by a group selected from K; R¹ is a substituenton carbon and is selected from halo, amino, C₁₋₆alkyl, C₁₋₆alkoxy,N—(C₁₋₆alkyl)amino, aryl, aryloxy, arylC₁₋₆alkyl, heterocyclic group,(heterocyclic group)C₁₋₆alkyl, or a group (B-E-); wherein R¹, includinggroup (B-E-), may be optionally substituted on carbon by one or more W;and wherein if said heterocyclic group contains an —NH— moiety thatnitrogen may be optionally substituted by J; W is hydroxy, mercapto,C₁₋₆alkyl, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino or a group (B′-E′-);wherein W, including group (B′-E′-), may be optionally substituted oncarbon by one or more Y; Y and Z are independently selected from halo,nitro, cyano, hydroxy, C₁₋₆alkoxy, N,N—(C₁₋₆alkyl)₂amino orC₁₋₆alkanoylamino; G, J and K are independently selected from C₁₋₈alkyl,C₂₋₈alkenyl, C₁₋₈alkanoyl, aryl, arylC₁₋₆alkyl or (heterocyclicgroup)C₁₋₆alkyl; wherein G, J and K may be optionally substituted oncarbon by one or more Q; and wherein if said heterocyclic group containsan —NH— moiety that nitrogen may be optionally substituted by hydrogenor C₁₋₆alkyl; Q is cyano, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, aryl, aryloxy or a group(B″-E″-); wherein Q, including group (B″-E″-), may be optionallysubstituted on carbon by one or more Z; B, B′ and B″ are independentlyselected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkylC₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic group,(heterocyclic group)C₁₋₆alkyl, phenyl or phenylC₁₋₆alkyl; wherein B, B′and B″ may be optionally substituted on carbon by one or more D; andwherein if said heterocyclic group contains an —NH— moiety that nitrogenmay be optionally substituted by a group selected from G; E, E′ and E″are independently selected from —N(R^(a))—, —O—, —C(O)O—, —OC(O)—,—C(O)—, —N(R^(a))C(O)—, —N(R^(a))C(O)N(R^(a))—, —N(R^(a))C(O)O—,—OC(O)N(R^(a))—, —C(O)N(R^(a))—, —S(O)_(r)—, —SO₂N(R^(a))—,—N(R^(a))SO₂—; wherein R^(a) and R^(b) are independently selected fromhydrogen or C₁₋₆alkyl optionally substituted by one or more F and r is0-2; D and F are independently selected from halo, C₁₋₆alkoxy orN,N—(C₁₋₆alkyl)₂amino; m is 0, 1, 2, 3 or 4; wherein the values of R¹may be the same or different; R² is fluoro or chloro; n is 0, 1 or 2,wherein the values of R² may be the same or different; R³ is amino orhydroxy; R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, amino, carboxy or carbamoyl; p is 0, 1 or 2, whereinthe values of R⁴ may be the same or different; or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester or amide thereof.
 9. Acompound of formula (I) according to claim 1 wherein: Ring A ispyridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl, pyrimidin-6-yl,pyrimidin-5-yl, pyrimidin-4-yl, morpholin-4-yl, piperidin-4-yl,piperidin-3-yl, piperdin-2-yl, piperazin-4-yl, pyridazin-5-yl,pyrazin-6-yl, thiazol-2-yl, thien-2-yl, thieno[3,2d]pyrimidinyl,thieno[3,2b]pyrimidinyl, thieno[3,2b]pyridinyl, purin-6-yl ortriazin-6-yl; wherein if Ring A contains an —NH— moiety that nitrogenmay be optionally substituted by a group selected from K; R¹ is asubstituent on carbon and is selected from fluoro, chloro, amino,methyl, ethyl, propyl, methoxy, N-methylamino, N-ethylamino,N-propylamino, N-butylamino, phenyl, naphthylethyl, piperazin-1-yl,piperidin-1-yl, piperidin-4-yl, 2-(thiomethyl)-pyrimidin-4-yl,tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl,1,2,5-thiadiazol-3-ylethyl, piperidin-1-ylmethyl, pyridin-2-ylmethyl, ora group (B-E-); wherein R¹, including group (B-E-), may be optionallysubstituted on carbon by one or more W; and wherein if said heterocyclicgroup contains an —NH— moiety that nitrogen may be optionallysubstituted by J; W is hydroxy, methyl, ethyl, ethoxy,N,N-(diethyl)amino, N,N-(dibutyl)amino, or a group (B′-E′-); wherein W,including group (B′-E′-), may be optionally substituted on carbon by oneor more Y; Y and Z are independently selected from fluoro, chloro,bromo, nitro, cyano, hydroxy, methoxy, N,N-(dimethyl)amino ormethylcarbonylamino; G, J and K are independently selected from methyl,ethyl, propyl, pentyl, 2-methylbutyl, butyl, acetyl, benzyl,3-(pyrrol-1-yl)propyl or pyrrolidin-2-one-(5S)-methyl; wherein G, J andK may be optionally substituted on carbon by one or more Q; and whereinif said heterocyclic group contains an —NH— moiety that nitrogen may beoptionally substituted by hydrogen or methyl; Q is cyano, hydroxy,methoxy, ethoxy, methylcarbonyloxy, methoxycarbonyl,t-butoxycarbonylamino, phenyl or a group (B″-E″-); wherein Q, includinggroup (B″-E″-), may be optionally substituted on carbon by one or moreZ; B, B′ and B″ are independently selected from methyl, ethyl, propyl,cyclohexyl, phenyl, benzyl, 1,2,3,4-tetrahydroquinolinyl,3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl,3-morpholinopropyl, 3-(4-methylpiperazin-1-yl)propyl,2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl orimidazol-1-ylpropyl; wherein B, B′ and B″ may be optionally substitutedon carbon by one or more D; and wherein if said heterocyclic groupcontains an —NH— moiety that nitrogen may be optionally substituted by agroup selected from G; E, E′ and E″ are independently selected from—N(R^(a))—, —O—, —C(O)—, —NHC(O)—, —N(R^(a))C(O)O—; wherein R^(a) ishydrogen or methyl optionally substituted by one or more F; D and F areindependently selected from fluoro, methoxy or ethoxy; m is 0, 1, or 2;wherein the values of R¹ may be the same or different; R² is fluoro; nis 0 or 1; R³ is amino; R⁴ is halo; p is 0, 1 or 2, wherein the valuesof R⁴ may be the same or different; or a pharmaceutically acceptablesalt or in vivo hydrolysable ester or amide thereof.
 10. A process forpreparing a compound of formula (I) or a pharmaceutically acceptablesalt or an in vivo hydrolysable ester thereof, according to claim 1,which process comprises of: (a) the reaction of a compound of theformula (II)

wherein X is a reactive group, with a compound of the formula (III)

wherein L¹ and L² are ligands; (b) the reaction of a compound of theformula (IV)

wherein L¹ and L² are ligands, with a compound of the formula (V)

wherein X is a reactive group; or (c) the reaction, in the presence of4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride, ofa compound of the formula (VI)

with a compound of the formula (VII)

and thereafter if necessary: i) converting a compound of the formula (I)into another compound of the formula (I); and/or ii) removing anyprotecting groups.
 11. A pharmaceutical composition which comprises acompound of the formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester or amide thereof, according to any one of claims1 to 9 in association with a pharmaceutically-acceptable diluent orcarrier. 12-13. (canceled)
 14. A method for producing a HDAC inhibitoryeffect in a warm-blooded animal in need thereof, which comprisesadministering to said animal an effective amount of a compound of theformula (I), or a pharmaceutically acceptable salt or in vivohydrolysable ester or amide thereof, according to any one of claims 1 to9.
 15. (canceled)
 16. A method of treating cancer in a warm-bloodedanimal in need of such treatment which comprises administering to saidanimal an effective amount of a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester or amidethereof, according to any one of claims 1 to
 9. 17. (canceled)